Butyric acid derivatives for treating pain and inflammation

ABSTRACT

Novel butyric acid derivatives of the formula ##SPC1## 
     Wherein X, X 1 , X 2  and X 3  are individually selected from the group consisting of hydrogen, halogen, lower alkyl of 1 to 5 carbon atoms, lower alkoxy of 1 to 5 carbon atoms, lower alkylthio of 1 to 5 carbon atoms, trifluoromethoxy, trifluoromethylthio, trifluoromethyl, OH and dilower alkylamino of 1 to 5 carbon atoms for each alkyl, R is selected from the group consisting of hydrogen, lower alkyl of 1 to 5 carbon atoms, o-carboxyphenyl, 2,3-dihydroxypropyl and ##EQU1## wherein P and Q are individually lower alkyl of 1 to 5 carbon atoms, Z and X 4  are individually selected from the group consisting of hydrogen and lower alkyl of 1 to 5 carbon atoms and Y is selected from the group consisting of hydrogen and --CH and the dotted line indicates the optional presence of a double bond when Y is hydrogen and when R is hydrogen or o-carboxyphenyl, the salts thereof with a non-toxic pharmaceutically acceptable mineral or orgaic base, which compounds have anti-inflammatory and analgesic activity and are substantially devoid of ulcerigenic activity and their preparation and novel intermediates formed therein.

PRIOR APPLICATION

This application is a division of copending, commonly assignedapplication Ser. No. 284,575 filed Aug. 29, 1972, now U.S. Pat. No.3,931,302.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel butyric acidderivatives of formula I and their salts with a non-toxic,pharmaceutically acceptable base where appropriate.

It is a further object of the invention to provide a novel process forthe preparation of the butyric acid derivatives of formula I and toprovide novel intermediates produced therein.

It is another object of the invention to provide novel analgesic andanti-inflammatory compositions.

It is an additional object of the invention to provide a novel method ofrelieving pain and inflammation in warmblooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel butyric acid derivatives of the invention are selected fromcompounds of the formula ##SPC2##

Wherein X, X₁, X₂ and X₃ are individually selected from the groupconsisting of hydrogen, halogen, lower alkyl of 1 to 5 carbon atoms,lower alkoxy of 1 to 5 carbon atoms, lower alkylthio of 1 to 5 carbonatoms, trifluoromethoxy, trifluoromethylthio, trifluoromethyl, OH anddilower alkylamino of 1 to 5 carbon atoms for each alkyl, R is selectedfrom the group consisting of hydrogen, lower alkyl of 1 to 5 carbonatoms, O-carboxyphenyl, 2,3-dihydroxypropyl and ##STR1## wherein P and Qare individually lower alkyl of 1 to 5 carbon atoms, Z and X₄ areindividually selected from the group consisting of hydrogen and loweralkyl of 1 to 5 carbon atoms and Y is selected from the group consistingof hydrogen and --OH and the dotted line indicates the optional presenceof a double bond when Y is hydrogen and when R is hydrogen oro-carboxyphenyl, and salts thereof with a non-toxic, pharmaceuticallyacceptable mineral or organic base.

In the compounds of the formula, X, X₁, and X₂ and X₃ can be in anypossible position on the benzene rings and when they are halogen, theyare preferably fluorine or chlorine and when they are alkyl, alkoxy oralkylthio, they are preferably methyl, ethyl, n-propyl, methoxy, ethoxy,methylthio or ethylthio. When there is a double bond present in thebutyric acid chain, the compounds of formula I may be cis isomers ortrans isomers.

Examples of non-toxic, pharmaceutically acceptable salts when R ishydrogen or o-carboxyphenyl are alkali metal salts such as sodium,potassium or lithium, alkaline earth metal salts such as calcium,ammonium or amine salts such as triethylamine.

Among the preferred compounds of formula I are those having a formulaselected from the group consisting of ##SPC3##

wherein X and X₂ are individually selected from the group consisting ofhydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbonatoms, alkylthio of 1 to 5 carbon atoms, trifluoromethyl,trifluoromethoxy and trifluoromethylthio, R is selected from the groupconsisting of hydrogen, alkyl of 1 to 5 carbon atoms, 2,3-dihydroxypropyl and ##STR2## wherein P and Q are individually alkyl of1 to 5 carbon atoms and X₄ and Z have the above definitions and thenon-toxic, pharmaceutically acceptable salts thereof where R ishydrogen, ##SPC4##

wherein X, X₂, X₄, Y, Z and R have the above definitions with the dottedline representing, when Y is hydrogen, a double bond in either αβ or βγto the carboxylic group and the non-toxic, pharmaceutically acceptablesalts thereof when R is hydrogen, and ##SPC5##

wherein X, X₂ and R have the above definitions and the non-toxic,pharmaceutically acceptable salts thereof when R is hydrogen.

The most preferred compounds of formula I are4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid and4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-2-butenoic acid.

The novel process of the invention depends upon the nature of theparticular substituents. The process for the preparation of compounds offormula Ia comprises reacting a m-benzoylphenyl-propionic acid of theformula ##SPC6##

wherein X, X₂ and Z have the definition as in formula Ia with achlorinating agent to form the corresponding acid chloride of theformula ##SPC7##

reacting the latter with a diazoalkane of the formula X₄ --CHN₂ whereinX₄ has the above definition to obtain a diazoketone of the formula##SPC8##

reacting the latter with a compound of the formula R₁ OH wherein R₁ isselected from the group consisting of hydrogen, alkyl of 1 to 5 carbonatoms and ##STR3## and P and Q have the above definitions to obtain acompound of the formula ##SPC9##

which can be saponified to the free acid or into an ester bytransesterification or esterification or into a salt and when R₁ is##STR4## can be subjected to acid hydrolysis to obtain the corresponding2,3-dihydroxypropyl ester.

In a preferred embodiment of the process, the chlorination agent isthionyl chloride, oxalyl chloride, phosphorus trichloride and phosphoruspentachloride and the rearrangement of the diazoketone of formula IV iseffected preferably in the presence of a metal catalyst such as a silverbase catalyst, i.e. silver oxide or silver benzoate or simply byheating.

The starting material of formula II can be prepared by methods analogousto those described in French BSM patent No. 8440 M. To obtain a compoundof formula II in which Z is hydrogen, an alkyl malonate is reacted witha 3-bromomethyl-benzophenone and the corresponding malonic acidderivative is subjected to acid hydrolysis and a decarboxylation. Toobtain a compound of formula II in which Z is alkyl, the desiredm-benzoylphenyl-acetonitrile is reacted with an alkylating agent toobtain the corresponding m-benzoyl-α-alkyl-phenyl-acetonitrile and thelatter is subjected to acid hydrolysis to form them-benzoyl-α-alkylphenylacetic acid and the latter is homologated by theArndt-Eistert method to form the correspondingm-benzoyl-phenyl-propionic acid.

The m-benzoyl-phenyl-acetic acids can also be prepared and the α-alkylderivatives thereof by the methods described in French patent No.1,516,775 and Belgian patent No. 718.466. The esters of m-benzoyl-phenylacetic acids can be α-alkylated by reaction with an alkaline agent andthen alkyl iodide. The m-benzoyl-phenyl-acetic acid can be homolgatedsuch as by the Arndt-Eistert method to form the correspondingm-benzoyl-phenyl-propionic acids of formula II. Another method ofobtaining compounds of formula II with alkyl substituents on the benzenering is illustrated in Example IV.

The process for the preparation of compounds of formula Ib comprisesreacting an M-benzoyl-phenyl-acetic acid of the formula ##SPC10##

wherein X, X₂ and Z are defined as in formula Ib with a chlorinatingagent to form the corresponding acid chloride, reacting the latter witha diazoalkane of the formula X₄ -CHN₂ wherein X₄ has the abovedefinition to form a diazoketone of the formula ##SPC11##

reacting the latter with an anhydrous hydrogen halide to form ahalomethylketone of the formula ##SPC12##

wherein Hal is a halogen, treating the latter with a reducing agent toform a diol of the formula ##SPC13##

reacting the latter with an alkali metal cyanide to form a nitrile ofthe formula ##SPC14##

reacting the latter with a selective oxidizing agent to obtain acompound of the formula ##SPC15##

reacting the latter with a compound of the formula R₂ OH wherein R₂ isselected from the group consisting of hydrogen and alkyl of 1 to 5carbon atoms to form a compound of the formula ##SPC16##

which, if desired, when R₂ is alkyl of 1 to 5 carbon atoms, is subjctedto the action of a dehydrating agent to form a compound of the formula##SPC17##

with the double bond αβ or βγ to the carboxylic group, separating ifnecessary the unsaturated αβ and βγ isomers and subjecting if desiredthe product of formula Ib' and Ib" to a saponification ortransesterification when R₂ is alkyl of 1 to 5 carbon atoms or asalification or esterification when R₂ is hydrogen and then when R₂ is2,3-(P,Q-methylenedioxy)-propyl, the product can be subjected to acidhydrolysis to form the corresponding 2,3-dihydroxypropyl derivative. Thecompounds of formula Ib when having a double bond can be trans or cisisomeric form.

In preferred embodiments of the process, the chlorination agent may bethionyl chloride, oxalyl chloride, phosphorus trichloride or phosphoruspentachloride; the reducing agent is an aluminum alcoholate, notablyaluminum isopropylate or aluminum tert.-butylate; the selectiveoxidizing agent is manganese dioxide, silver silicate and preferablychromic anhydride; and the dehydrating agent is p-toluene sulfonic acidand preferably phosphoric acid anhydride and may be operated by heatingin xylene. The dehydrated products generally occur as a mixture of αβand βγ isomers which can be separated by known physical methods.

The process for preparation of compounds of formula Ic comprisesreacting a compound of the formula ##SPC18##

with an alkyl acetylacetate of the formula ##STR5## wherein R₃ is alkylof 1 to 5 carbon atoms to form a compound of the formula ##SPC19##

subjecting the latter to hydrolysis and decarboxylation in an acid mediato obtain a compound of the formula ##SPC20##

and reacting the latter with sulfur and a primary or secondary amine andhydrolyzing the product to obtain a compound of formula Ic wherein R ishydrogen. The said acid can then be salified or esterified and theneventually transesterified to obtain the 2,3-(P,Q-metylenedioxy)-propylester which may be acid hydrolyzed to obtain the corresponding2,3-dihydroxypropyl ester.

In a preferred mode of the process, the hydrolysis and decarboxylationreaction is effected by heating in the presence of an aqueous acid suchas hydrochloric acid, sulfuric acid, acetic acid or a mixture of saidacids and the amine used for reaction with sulfur is preferablymorpholine.

The bromomethyl compounds of formula XII may be prepared by analogousmethods to those described in French patent No. 1,546,478 and Belgianpatent. No. 718,466.

The novel intermediates of the invention are compounds having a formulaselected from the group consisting of ##SPC21##

wherein X, X₂ and Z have the above definitions and when A₂ is CH₂ --Hal,Hal is a halogen A and A₁ are identical and are selected from the groupconsisting of =O and ##STR6## and when A₂ is CH₂ CN, A₁ is ##STR7## andA is selected from the group consisting of ##STR8## and =O and ##SPC22##

wherein X and X₂ have the above definition and D is selected from thegroup consisting of H and --COOAlk wherein Alk is alkyl of 1 to 5 carbonatoms.

In a variation of the process to produce the compounds of formula Iwherein X, X₁, X₂ and X₃ have the above definition and X₄, Y, Z and Rare hydrogen and a double bond optionally exists αβ to the carboxylicgroup and the salts thereof comprises reacting a compound of the formula##SPC23##

wherein the X's have the above definition with alkali metal nitrite suchas sodium nitrite in the presence of a mineral acid such as hydrochloricacid to form the corresponding diazonium salt thereof, reacting thelatter with 1,3-butadiene to obtain a 1-chloro-butene-2 of the formula :##SPC24##

reacting the latter with an alkali metal acetate in the presence ofacetic acid to obtain the corresponding 1-acetoxybutene-2-compound whichis saponified with an alkali metal hydroxide to form the corresponding1-hydroxy-butene-2-compound and either subjecting the latter to hydrogenin the presence of a metallic catalyst to form the corresponding1-hydroxy-butane compound which can be oxidized with an oxidizing agentto form the corresponding butyric acid compound which can be salified oroxidizing the latter with an oxidizing agent to obtain the corresponding2-butenoic acid which may be salified if desired.

This modified process can be used to prepare4-(3'-p-trifluoromethoxybenzoyl-2'-methyl-phenyl)-butyric acid,4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butyric acid and4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-2-butenoic acid.

Another modification of the process comprises reacting 3-bromo-1-propenewith methyl 2-hydroxybenzoate to obtain methyl2'-(3-oxy-1-propene)-benzoate, hydrolyzing the latter to form the freeacid, reacting the latter with a chlorinating agent such as thionylchloride to form the corresponding acid chloride, condensing the latterwith cadmium chlorophenyl to form3-(2'-p-chlorobenzoyl-phenyl)oxy-1-propene, heating the latter to form3-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-propene, reacting the latterwith an oxidizing atent to form2-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-oxo-ethane, condensing thelatter with malonic acid, decarboxylating the resulting dicarboxylicacid to form 4-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-2-butenoic acidand hydrogenating the latter in the presence of palladium to obtain4-(3'-p-chlorobenzoyl-2-'-hydroxyphenyl)-butyric acid and finally withan oxidizing agent to form4-(3'-p-chlorobenzoyl-2',5'-dihydroxy-phenyl)-butyric acid.

4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid may be reactedeither with an alkoxylation agent such as a methoxylation agent to form4-(3'-p-alkoxybenzoyl-2'-methyl-phenyl)-butyric acid or with adialkylamine such as dimethylamine to obtain4-(3'-dialkylaminobenzoyl-2'-methyl-phenyl)-butyric acid. The4-(3'-chlorobenzoyl-2'-methyl-phenyl)-butyric acid may also be reactedwith a chlorinating agent such as thionyl chloride to form thecorresponding acid chloride and the latter may be reacted with salicylicacid to form o-carboxyphenyl4-(3'-p-chlorobenzoyl-2'-methylphenyl)-butyric acid ester.

4-(m-benzoyl-phenyl)-2-methyl-butyric acid may be reacted with firstbromine in the presence of phosphorus bromide and then with methanol toobtain methyl 4-(m-benzoyl-phenyl)-2-methyl-2-bromo-butanoate,subjecting the latter to dehydrobromination to form methyl4-(m-benzoyl-phenyl)-2-methyl-2-butenoate which is subjected to acidhydrolysis to form 4-(m-benzoyl-phenyl)-2methyl-2-butenoic acid.4-(m-benzoyl-phenyl)-4-methyl-3-butenoic acid may be hydrogenated in thepresence of a metallic catalyst to form4-(m-benzoyl-phenyl)-4-methyl-butyric acid.

The novel anti-inflammatory and analgesic compositions of the inventionwhich are substantially devoid of ulcerigenic effect are comprised of aneffective amount of at least one compound of formula I or its non-toxic,pharmaceutically acceptable salts where appropriate, and apharmaceutical carrier. The compositions may be in the form ofinjectable solutions or suspensions in ampoules or multiple dose flaconsor in the form of tablets, coated tablets, capsules, syrups,suppositories or pomades prepared in the usual manner.

The compositions are useful for the treatment of rheumatic affections,arthrosis, lombalgies, sciatics, neuralgial, myalgies or toothaches.

The novel method of the invention for the treatment of pain andinflammation in warm-blooded animals comprises administering towarm-blooded animals an effective amount of at least one compound offormula I or its non-toxic, pharmaceutically acceptable salts when R ishydrogen or o-caboxyphenyl. The said compounds may be administeredparenterally, orally, rectally or locally by topical application on skinor mucosa. The usual daily dose is 2 to 20 mg/kg depending upon thespecific product and the method of administration.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE I 4-(m-benzoyl-phenyl)-butyric acid

Step a: ethyl m-benzoyl benzyl malonate

A mixture of 32 g of 3-methyl-benzophenone (process of Ador et al,Berichte, Vol. 12, p. 2299), 96 ml of carbon tetrachloride, 26 g ofN-bromosuccinimide and 100mg of benzoyl peroxide was refluxed for onehour and after the addition of another 100mg of benzoyl peroxide, themixture was refluxed for 1 hour. Another 100 mg of benzoyl peroxide wereadded and reflux was maintained for 11/2 hours. Another 100 mg ofbenzoyl peroxide were added and reflux was maintained with stirring for11/2 hours. The mixture was cooled, filtered and the filtrate wasdistilled to dryness under reduced pressure to obtain 46 g of3-bromomethyl-benzophenone which was used as is for the next step.

3.84 g of sodium were dissolved with stirring into 100 ml of ethanol andafter the addition of 25 ml of ethyl malonate, the mixture was heated toreflux. 46 g of 3-bromomethyl-benzophenone in 46 ml of ethanol were thenprogressively added thereto and the mixture was then refluxed for 3hours and concentrated under reduced pressure. 100 ml of water wereadded thereto and the mixture was extracted with methylene chloride. Theorganic phase was washed with water and distilled under reducedpressure. The liquid residue was purified by distillation to obtain 16.5g of ethyl m-benzoyl-benzyl-malonate in the form of a colorless liquidhaving a boiling point of 216°-218° C at 0.7 mm Hg. The product wassoluble in alcohol, chlorinated solvents and benzene and insoluble inwater.

Analysis: C₁₂ H₂₂ O₅ ; molecular weight = 354.41.

Calculated: %C, 71.17; %H, 6.26.

Found: %, 71.5; %H, 6.2.

I.R. Spectrum (chloroform): Presence of C=O at 1730 and 1745.sup. cm⁻ 1and of conjugated ketone at 1661.sup. cm⁻ 1.

Step b: 3-(m-benzoyl-phenyl)-propionic acid

A solution of 16 g of ethyl m-benzoyl-benzyl-malonate, 160 ml of 57%hydroiodic acid and 320 ml of acetic acid was refluxed for 2 hours andthen the acetic acid and hydroiodic acid were distilled off. The residuewas taken up in water and the aqueous phase was extracted with ethylacetate. The organic phase was washed with an aqueous sodium chloridesolution, dried over magnesium sulfate and distilled to dryness underreduced pressure. The residue was dissolved in a minimum of ether andthe solution was filtered through a column of magnesium silicate andeluted with ether. The eluant was distilled to dryness under reducedpressure and the raw product was redissolved in 200 ml of ether. Thesolution was filtered and after the addition of 4.5 ml ofcyclohexylamine, the mixture was iced for 30 minutes and was vacuumfiltered. The precipitate was washed with water and dried to obtain 13 gof the cyclohexylamine salt of 3-(m-benzoyl-phenyl)propionic acidmelting at 140° C.

The said salt was purified by dissolution in 5 volumes of hot methanol,adding 10 volumes of ethyl acetate, filtering and concentration to 5volumes while adding ethyl acetate to replace methanol. After icing for1 hour, the mixture was vacuum filtered and the precipitate was washedwith water and dried to obtain 11 g of pure cyclohexylamine salt with anunchanged melting point. The said cyclohexylamine salt was suspended inethyl acetate and after acidification of the mixture by addition of 20ml of 2N hydrochloric acid, the mixture was decanted. The organic phasewas washed with water, reextracted with ethyl acetate, dried overmagnesium sulfate and distilled to dryness under reduced pressure. Theresidue was taken up in a minimum of ether and the solution was passedthrough magnesium silicate. The solution was filtered, concentrated to 2volumes and after the addition of 4 volumes of pentane, the mixture wasconcentrated while adding pentane until 30 ml of distillate wereobtained. Crystallization was started and after icing for 1 hour, thereaction mixture was vacuum filtered. The recovered precipitate waswashed with pentane and dried to obtain 5.8 g. of3-(m-benzoyl-phenyl)-propionic acid melting at 70° C. The productoccurred in the form of a colorless solid soluble in chlorinatedsolvents, alcohols, ethyl acetate, benzene and ether and insoluble inwater.

Analysis: C₁₆ H₁₄ O₃ ; molecular weight = 254.27.

Calculated: %C, 75.57; %H, 5.55.

Found: %C, 75.7, %H, 5.8.

I.R. Spectrum: Presence of acid carbonyl at 1712^(cm) ⁻¹ and conjugatedketone at 1660^(cm) ⁻¹.

Step c: 3-(m-benzoyl-phenyl)-propionyl chloride

A mixture of 18.15 g of 3-(m-benzoyl-phenyl)-propionic acid and 25 ml ofthionyl chloride was refluxed for 11/2 hours and excess thionyl chloridewas removed under reduced pressure to obtain3-(m-benzoyl-phenyl)-propionyl chloride which was used as is for thenext step.

Step d: 3-(4'-diazo-3'-oxo-butyl)-benzophenone

A solution of the acid chloride of Step C in 200 ml of methylenechloride was cooled to 0° C and then 400 ml of methylene chloridecontaining 29.5 g/liter of diazomethane was added thereto at atemperature not greater than 3° C. The mixture was allowed to return toroom temperature and was stirred overnight. The methylene chloride wasdistilled off and the mixture was evaporated to dryness to obtain3-(4'-diazo-3'-oxobutyl)-benzophenone.

Step e: 4-(m-benzoyl-phenyl)-butyric acid

A suspension of 24.43 g of silver oxide, 59.37 g of sodium carbonate and39.01 g of sodium thiosulfate in 270 ml of water was heated to 60° C andthe diazoketone of Step D in 126 ml of dioxane was added thereto. Thereaction mixture was refluxed for 11/2 hours and was then cooled andfiltered. The separated aqueous phase was adjusted to a pH of 1 byaddition of 60 ml of nitric acid and was extracted with ether. The etherphase was dried over magnesium sulfate and evaporated to dryness underreduced pressure. The residue was purified by crystallization fromisopropyl ether to obtain 6.7 g of 4-(m-benzoyl-phenyl)-butyric acidmelting at 71° C. The product was soluble in chloroform, methylenechloride, methanol and dilute alkalis and insoluble in water.

Analysis: C₁₇ H₁₆ O₃ ; molecular weight = 268.31.

Calculated: %C, 76.10; %H, 6.01.

Found: %C, 75.9; %H, 5.9.

RMN Spectrum (CCl₄): Aromatic protons -435 to 470 Hz; hydroxyl ofcarboxyl -599 Hz; hydrogens of aliphatic chain - Cα -127, 129 and 139 HzCβ- 108, 115, 123 and 129 Hz Cγ-154, 161 and 163 Hz.

EXAMPLE II 2,3-isopropylidenedioxypropyl 4-(m-benzoyl-phenyl)-butyrate

Step a: 3-(4'-diazo-3'-oxo-butyl)-benzophenone

A mixture of 10 g of 3-(m-benzoyl-phenyl)-propionic acid and 50 ml ofoxalyl chloride was stirred for 4 hours at room temperature and theexcess oxalyl chloride was removed under reduced pressure. The resultingoil was taken up twice in 50 ml of benzene and evaporated to drynessunder reduced pressure to obtain 10.7 g of3-(m-benzoyl-phenyl)-propionyl chloride identical to Example I.

A solution of the said acid chloride in 50 ml of anhydrous methylenechloride was added with stirring in one hour at 0° C to 550 ml ofmethylene chloride solution containing 8.2 g/liter of diazomethane andafter standing overnight, the mixture was allowed to return to 20° C.The mixture was evaporated to dryness under reduced pressure to obtain11.25 g of 3-(4'-diazo-3'-oxo-butyl)-benzophenone identical to that ofExample I.

Step b: 2,3-isopropylidenedioxypropyl 4-(m-benzoyl-phenyl)-butyrate

A solution of 1 g of silver benzoate in 12.5 ml of triethylamine wasadded dropwise with stirring to a solution of 11.25 g of the diazoketoneof Step A in 80 ml of redistilled and anhydrous2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and stirring was continueduntil nitrogen evolution ceased. Another few drops of the said solutionwere added until there was no nitrogen evolution and then a pinch ofsilver benzoate was added to verify that the reacton was complete. Thereaction mixture was poured with stirring into 300 ml of water and themixture was filtered to remove silver salts. The insolubles were washed4 times with 100 ml of isopropyl ether that was utilized to wash theaqueous phase. The obtained organic phase was washed 4 times with 100 mlof water, dried over sodium sulfate, decolorized with activated carbon,filtered and evaporated to dryness under reduced pressure to obtain13.05 g of a yellow oil. The oil was purified by chromatography oversilica gel and elution with methylene chloride containing 0.1% oftriethylamine to obtain 8.18 g 2,3-isopropylidenedioxypropyl4-(m-benzoyl-phenyl)-butyrate in the form of a yellow oil.

Microanalysis (effected after the product was dried at 150° C)

C₂₃ H₂₆ O₅ ; molecular weight = 382.44.

Calculated: %C, 72.23; %H, 6.85.

Found: %C, 72.0; %H, 6.9.

I.R. Spectrum: In accordance with the structure, presence of a peakcorresponding to ester function at 1739^(cm) ⁻¹.

EXAMPLE III 2,3-dihydroxypropyl 4-(m-benzoyl-phenyl)-butyrate

A mixture of 8.18 g of the ester prepared in Example II, 41 ml ofmethoxyethanol and 13 g of crystalline boric acid was heated to 100° Cwith stirring and was stirred for 3 hours at the said temperature andthen was iced. The white precipitate formed was eliminated and themixture was filtered. The filtrate was added to 400 ml of water withstirring and the mixture was washed with ether. The organic phase waswashed with 40 ml of a saturated aqueous sodium bicarbonate solution andthen was diluted with 400 ml of methylene chloride. The mixture wasdried over sodium sulfate, decolorized with activated charcoal, filteredand evaporated to dryness under reduced pressure to obtain 7.5 g of ayellow oil. The oil was purified by chromatography over silica gel andelution with ethyl acetate to obtain 5.56 g of 2,3-dihydroxypropyl4-(m-benzoyl-phenyl)-butyrate in the form of a colorless oil.

Analysis: C₂₀ H₂₂ O₅ ; molecular weight = 342.38.

Calculated: %C, 70.16; %H, 6.48.

Found: %C, 70.1; %H, 6.7.

I.R. Spectrum: In accordance with the structure, presence of a peakcorresponding to a free hydroxy at 3601^(cm) ⁻¹. Carbonyl: conjugatedketone at 1660 and 1651^(cm) ⁻¹ and ester at 1733^(cm) ⁻¹. Aromatic ringat 1601 - 1584 - 1481^(cm) ⁻¹.

EXAMPLE IV 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methylphenyl)-butyrate

Step a: 2-methyl-3-nitro-4'chloro-benzophenone

100 g of 2-methyl-3-nitro-benzoic acid and 500 ml of thionyl chloridewere refluxed for 15 hours and the mixture was then evaporated todryness under reduced pressure to obtain 110 g of2-methyl-3-nitro-benzoyl chloride which was used as in the synthesis.

A mixture of 30 g of magnesium and 450 ml of ether was refluxed and thena solution of 191 g of p-chlorobromobenzene in 600 ml of ether wasslowly added and reflux was continued for 11/2 hours after the addition.The mixture was cooled to 20° C to obtain an ether solution of 0.7Np-chlorophenyl magnesium bromide. After cooling 800 ml of the solutionto 10° C, 55.7 g of cadmium chloride were added thereto and the etherwas distilled off while adding benzene as a replacement. After obtaining1 1 of distillate, it was cooled to 8° C and a solution of 110 g of2-methyl-3-nitro-benzoyl chloride in 550 ml of benzene was addedthereto. The mixture stood for 18 hours and was then added to a mixtureof 3,650 ml of icewater and 134 ml of hydrochloric acid. The mixture wasfiltered and the benzene phase was decanted. The aqueous phase wasextracted with benzene and the combined benzene phases were washed withN hydrochloric acid, with water, with saturated aqueous sodiumbicarbonate and finally with water. The organic phase was dried oversodium sulfate and evaporated to dryness under reduced pressure toobtain 147.3 g of 2-methyl-3-nitro-4'-chloro-benzophenone which was usedas is in the next step.

For analysis, 13 g of the product were chromatographed over silica geland eluted with methylene chloride and evaporation of the eluant gave8.13 g of pure product in the form of a chestnut oil soluble inmethylene chloride and ether and insoluble in water.

Analysis: C₁₄ H₁₀ ClNO₃ ; molecular weight = 275.69.

Calculated: %C, 60.99; %H, 3.65; %Cl, 12.86; %N, 5.08.

Found: %C, 60.0, %H, 4.0; %Cl, 11.4; %N, 5.2.

I.R. Spectrum (chloroform): Presence of conjugated ketone, aromatic andNO₂

Step b: 2-methyl-3-amino-4'-chloro-benzophenone

A mixture of 3,750 ml of hydrochloric acid, 134 g of2-methyl-3-nitro-4'-chloro-benzophenone and 536 g of stannous chloridewas heated at 62° C for 6 hours and was then cooled to 5° C and heldtherefor 1 hour. The mixture was vacuum filtered and the precipitate waswashed with hydrochloric acid and dried under reduced pressure. Theresidue was stirred for 2 hours at room temperature with 1,300 ml ofwater, 1,000 ml of 2N sodium hydroxide and 230 ml of ether and themixture was then extracted with methylene chloride. The organic phasewas washed with water, dried over sodium sulfate and evaporated todryness under reduced pressure to obtain 68.7 g of2-methyl-3-amino-4'-chloro-benzophenone melting at 65° C which was usedas is for the next step.

For analysis, 4.4 g of the raw product were chromatographed over silicagel with elution with a 90:10 methylene chloride-ether mixture andevaporation of the eluant gave 4 g of the product melting at 68° C. Theproduct occurred in the form of beige crystal soluble in methylenechloride and methanol and insoluble in water.

Analysis: C₁₄ H₁₂ ClNO; molecular weight = 245.70.

Calculated: %C, 68.44; %H, 4.92; %Cl, 14.43.

Found: %C, 68.4; %H, 5.0; %Cl, 14.7.

I.R. Spectrum (chloroform): Presence of conjugated ketone at 1660^(cm)⁻¹, of aromatic and NH₂ at 1617 and 1582^(cm) ⁻¹ and of NH₂.

Step c: 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-2-chloro-propionic acid

A suspension of 67.5 g of 2-methyl-3-amino-4'-chlorobenzophenone in 250ml of water had added thereto 88 ml of hydrochloric acid and the mixturewas stirred for 20 minutes at 25° to 28° C and was then cooled to 5° C.A solution of 20.4 g of sodium nitrite in 40 ml of water was addedthereto and the mixture was stirred for 30 minutes at 5° C and was thenvacuum filtered to obtain a solution of2-methyl-4'-chlorobenzophenone-3-diazonium chloride.

The said solution was then added to a mixture of 340 ml of acetone, 5.4g of cuprous chloride and 54 ml of acrylic acid heated to 46° C and themixture was stirred for 30 minutes. After the evolution of 5 liter ofnitrogen, the temperature was returned to 20° C and 3,000 ml ofmethylene chloride was added thereto. The organic phase was washed withwater, dried over sodium sulfate and evaporated to dryness under reducedpressure. The residue was dissolved in 800 ml of an aqueous saturatedsodium bicarbonate solution and the solution was stirred for 10 minutes,was treated with activated carbon, stirred for another 10 minutes andwas vacuum filtered. The pH of the solution was adjusted 1 to 2 byaddition of 80 ml of hydrochloric acid with stirring at room temperatureand the mixture was extracted with methylene chloride. The organic phasewas washed with water, dried over sodium sulfate and evaporated todryness under reduced pressure to obtain 69 g of3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-2-chloropropionic acid which wasused as is for the next step.

For analysis, 6.7 g of the raw product was chromatographed over silicagel with a 49-49-2 mixture of benzene-ethyl acetate - methanol as eluantwhich was evaporated to obtain 2.17 g of the said product in the form ofa chestnut amorphous product soluble in methylene chloride.

Analysis: C₁₇ H₁₄ Cl₂ O₃ ; molecular weight = 337.21.

Calculated: %C, 60.55; %H, 4.18; %Cl, 21.03.

Found: %C, 60.6-60.5; %H 4.4-4.3, %Cl, 21.3-20.8.

I.R. Spectrum (chloroform): Presence of acid at 1725^(cm) ⁻¹, conjugatedketone at 1662^(cm) ⁻¹ and of aromatic.

Step d: 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionic acid

A mixture of 59 g of3-(3'-p-chlorobenzoyl-2'-methy-1-phenyl)-2-chloropropionic acid, 472 mlof acetic acid and 118 ml of water was heated to 75° C and after theaddition of 23.6 g of zinc, the mixture was held at 75° C for 21/2 hoursand returned to 20° C. The mixture was vacuum filtered and the reactionmixture was taken up in water and was extracted with methylene chloride.The organic phase was dried over sodium sulfate and was evaporated todryness under reduced pressure. The residue was chromatographed oversilica gel and was eluted with a 75-25 methylene chloride-ether mixture.Evaporation of the eluant gave 3 g of residue which was empasted with 6ml of isopropyl ether and vacuum filtered. The residue was washed withisopropyl ether and dried under reduced pressure to obtain 1 g of3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionic acid melting at144°-148° C which was used as is for the next step.

For analysis, the product was crystallized from isopropyl ether toobtain 570 mg of product in the form of colorless crystals melting at148° C. The product was soluble in chloroform and insoluble in water.

Analysis: C₁₇ H₁₅ ClO₃ ; molecular weight = 302.77.

Calculated: %C, 67.44; %H, 4.99; %Cl, 11.71.

Found: %C, 67.7; %H, 4.9; %Cl, 11.4.

I.R. Spectrum (chloroform): Presence of conjugated ketone at 1666^(cm)⁻¹, aromatic at 1587^(cm) ⁻¹, of carbonyl at 1703^(cm) ⁻¹ and of acid OHat 3494^(cm) ⁻¹.

Step e: 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionyl chloride

830 mg of 3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)propionic acid and 4.2ml of thionyl chloride were refluxed for 3 hours and then excess thionylchloride was distilled off and the last traces were removed byentrainment with benzene to obtain 876 mg of3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)propionyl chloride which was usedas is for the next step.

I.R. Spectrum (chloroform): Presence of C=O at 1795^(cm) ⁻¹ and1663^(cm) ⁻¹ and aromatic.

Step f: 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyrate

33 ml of a methylene chloride solution titrating 11 g/liter ofdiazomethane were added to a solution of 876 mg of3-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-propionyl chloride in 5 ml ofmethylene chloride at 5° C and the solution was allowed to stand for 18hours at room temperature and was then evaporated to dryness underreduced pressure to obtain 975 mg of3-(4"-diazo-3"-oxo-butyl)-2-methyl-4'-chloro-benzophenone.

I.R. Spectrum (Chloroform): Presence of CH=N^(+=N) ⁻ at 2105^(cm) ⁻¹ ofC=O at 1666 and 1661^(cm) ⁻¹, of conjugated ketone at 1643^(cm) ⁻¹ andof aromatic at 1587^(cm) ⁻¹.

A solution of 0.60 g of silver benzoate in 7.5 ml of triethylamine wasslowly added to a solution of 920 mg of the said diazoketone in 13 ml of2,2-dimethyl-4-hydroxymethyl1,3-dioxolane and the mixture was stirredfor 15 minutes at room temperature. After evolution of 50 ml ofnitrogen, the reaction mixture was poured into water and was extractedwith isopropyl ether. The organic phase was washed with water, driedover sodium sulfate and evaporated to dryness under reduced pressure.The residue was chromatographed over silica gel and eluted with a 95:5methylene chloride-ether mixture. Evaporation of the eluant yielded 525mg of 2,3-isopropylidenedioxy-propyl4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyrate in the form of a brownamorphous solid soluble in chloroform and insoluble in water.

Analysis: C₂₄ H₂₇ ClO₅ ; molecular weight = 430.93. Calculated: %C66.88; %H, 6.32; %Cl, 8.23. Found: %C, 66.8, %H, 6.3; %Cl, 7.9.

I.R. Spectrum (chloroform): Presence of ester carbonyl at 1736^(cm)≠1,of conjugated ketone at 1669^(cm) ⁻¹, of aromatic at 1590^(cm) ⁻¹ and of##STR9##

EXAMPLE V

A mixture of 6 g of 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyrate (Example IV), 60 ml ofethanol, 6 ml of water and 2.3 ml of 12.5N potassium hydroxide wasrefluxed for 2 hours and the methanol was removed at 50° C at a pressureof 20 mm Hg. The residue was dissolved in 60 ml of water and thesolution was treated with activated carbon and filtered. The pH of thefiltrate was adjusted to 1-2 by addition of 25 ml of 2N hydrochloricacid and after stirring for 1 hour at 15° C, the mixture was vacuumfiltered. The precipitate was washed with water and dried under reducedpressure to obtain 3.7 g of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid melting at 124° C. Theproduct occurred in the form of colorless crystals soluble in ethanol,slightly soluble in isopropyl ether and insoluble in water.

Analysis: C₁₈ H₁₇ ClO₃ ; molecular weight = 316.79. Calculated: %C,68.25; %H, 5.41; %Cl, 11.19. Found: %C, 67.9; %H, 5.4; %Cl, 11.3.

I.R. Spectrum (chloroform): Presence of acid dimer carbonyl at 1711^(cm)⁻¹, of conjugated ketone at 1668^(cm) ⁻¹ and aromatic at 1588^(cm) ⁻¹.

EXAMPLE VI

A mixture of 320 mg of 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyrate (Example IV), 1.5 ml ofmethoxy ethanol and 450 mg of boric acid was heated at 100° C for 1 hour15 minutes and after cooling to 20° C, the mixture was vacuum filteredand the filter was washed with isopropyl ether. The filtrate was addedto 10 ml of isopropyl ether and the organic phase was washed with asaturated aqueous solution of sodium bicarbonate and then with wateruntil the wash waters were neutral. The solution was dried over sodiumsulfate and evaporated to dryness and the residue was dissolved in 10 mlof methylene chloride. The solution was filtered and evaporated todryness to obtain 150 mg of 2,3-dihydroxypropyl4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyrate in the form of a clearyellow amorphous product soluble in chloroform and insoluble in water.

Analysis: C₂₁ H₂₃ ClO₅ ; molecular weight = 390.87. Calculated: %C,64.53; %H, 5.93; %Cl, 9.07. Found: %C, 64.5; %H, 6.2; %Cl, 9.3.

I.R. Spectrum (chloroform): Presence of C=O at 1733 and 1669^(cm) ⁻¹, ofaromatic at 1590 and 1486^(cm) ⁻¹, of OH at 3 580^(cm) ⁻¹ and ofassociated OH at 3450^(cm) ⁻¹.

EXAMPLE VII

17.5 g of 89% potassium methylate were added under an inert atmosphereto a suspension of 7.5 g of4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid (Example V) in 75ml of methanol and was then heated at 120°-130° C for 17 hours underpressure. After cooling to room temperature, the mixture was rinsed withwater and the methanol was eliminated under reduced pressure. Theresidue was dissolved in water, treated hot with activated carbon, icedand filtered. The filtrate was acidified to a pH of 1 with hydrochloricacid and the precipitate formed was recovered by filtration, was washedwith water until the wash water was neutral and dried. The residue wascrystallized from isopropyl ether to obtain 5.35 g of4-(3'-p-methoxybenzoyl-2'-methyl-phenyl)-butyric acid in the form ofcolorless crystals melting at 100° C and then 115° C.

Analysis: C₁₉ H₂₀ O₄ ; molecular weight= 312.35. Calculated: %C, 73.06;%H, 6.45; %OCH₃ 9.93. Found: %C, 73.1; %H, 6.4; %OCH, 10.0.

EXAMPLE VIII

Step a: 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid chloride

A mixture of 8 g of 4-(3'-p-chlorobenzoyl-2'-methylphenyl)-butyric acid(Example V) and 80 ml of thionyl chloride was refluxed for 45 minutesand after removal of excess thionyl chloride under reduced pressure, 60ml of benzene were added thereto. The traces of thionyl chloride wereremoved by entrainment with benzene. This operation was repeated 3times. The residue was taken up in tetra-hydrofuran to obtain a solutionof 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid chloride whichwas used as is for the next step.

Step b: o-carboxy phenyl 4-(3'-p-chlorobenzoyl-2'-methylphenyl)-butyrate

The acid chloride solution from Step A was added with stirring over 40minutes to a solution of 3.68 g of salicylic acid and 5.36 g oftriethylamine in 80 ml of tetrahydrofuran and the mixture was stirredovernight at room temperature. The triethylamine hydrochlorideprecipitate was removed by filtration and the filtrate was evaporatedunder reduced pressure. The residue was taken up in water and thesolution was extracted with ether. The aqueous phase cooled to 8° C, wasacidified by addition of N hydrochloric acid to a pH of 1 and theprecipitate formed was extracted with ether (extraction having aninsoluble A). The ether phase was washed with water, was dried overmagnesium sulfate and evaporated to dryness under reduced pressure. Theresidue was crystallized from toluene to obtain 0.6 g ofo-carboxyphenyl-4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyrate meltingat 165° C. Insoluble A was taken up in chloroform and the organic phasewas washed with water, dried over magnesium sulfate and evaporated todryness under reduced pressure. The residue was cristallized fromtoluene to obtain 1.5 g of the desired product for a total yield of 2.1g in the form of colorless crystals melting at 165° C.

Analysis: C₂₅ H₂₁ ClO₅ ; molecular weight = 436.87. Calculated: %C,68.72; %H, 4.84; %Cl, 8.12. Found: %C, 68.7; %H, 5.0; %Cl, 8.2.

EXAMPLE IX

Step a: 3-(4'-diazo-3'-oxo-pentyl)-benzophenone

Using the procedure of Step A of Example II, 22.98 g of3-(m-benzoyl-phenyl)-propionic acid and 115 ml of oxalyl chloride werereacted to obtain 24.59 g of 3-(m-benzoyl phenyl)-propionyl chloride. Asolution of the said acid chloride in 50 ml of anhydrous ether was addedwith stirring at 25° C in 45 minutes to 1,460 ml an ether solution of10.5 g/liter of diazomethane and the mixture was stirred at 25° C for 16hours and then evaporated to dryness under reduced pressure to obtain 29g of raw product which was purified by chromatography over silica with a95-5 methylene chloride-ethyl acetate eluant which was evaporated todryness to obtain 19 g of 3-(4'-diazo-3'-oxo-pentyl)-benzophenone. STEPB: 2,3-isopropylidenedioxypropyl 4-(m-benzoyl-phenyl)-2-methyl-butyrate

A solution of 19 g of the diazoketone from Step A in 190 ml ofredistilled 2,2-dimethyl-4-hydroxymethyl-1,3- dioxolane was heated withstirring at 170° C on a metallic bath and after the evolution of gasceased, the mixture was cooled to 20° C and poured with agitation into 1liter of water. The mixture was extracted 3 times with 250 ml ofisopropyl ether and the organic phase was washed 3 times with 150 ml ofwater, dried over sodium sulfate; decolorized with activated carbon,filtered and evaporated to dryness under reduced pressure to obtain 25.4g of an orange oil. The oil was purified by chromatography over silicaand elution with methylene chloride. Evaporation of the eluant todryness gave 9.07 g of 2,3-isopropylidenedioxypropyl4-(m-benzoyl-phenyl)-2-methylbutyrate in the form of a yellow oil.

Analysis: C₂₄ H₂₈ O₅ ; molecular weight = 396.46. Calculated: %C, 72.7;%H, 7.12.Found: %C, 72.9; %H, 6.8.

I.R. Spectrum: in accordance with the structure. Presence of bands inthe aromatic region at 1591 and 1582^(cm) ⁻¹, conjugated carbonyl at1650^(cm) ⁻¹, ester carbonyl at 1733^(cm) ⁻¹, presence of ketal.

RMN Spectrum: Signals corresponding to aromatic protons between 430 and470 Hz, methylene-α-to aromatic ring: signals at 154, 161, 169 Hz Ch -α - to CO signals between 130 and 170 Hz, Methyl α to carboxyl: signalat 69 and 75.5 Hz, ##STR10## signal at 80.5 to 84.5 Hz, CH₂ --CH--CH₂signal of 210 to 260 Hz.

EXAMPLE X

A mixture of 3.22 g of 2,3-isopropylidenedioxypropyl4-(m-benzoyl-phenyl)-2-methyl-butyrate (Step B of Example IX), 16 ml ofmethoxyethanol and 4.95 g of crystalline boric acid was heated withstirring to 100° C and held with stirring at 100° C for 2 hours. Aftercooling to 5° C, the insolubles were removed by filtration and thefilter was washed with ether. The filtrate was added with stirring to a160 ml of water at 20° C and the oil formed was extracted 3 times with30 ml of ether. The ether solution was washed with 30 ml of an aqueoussaturated sodium chloride solution and the organic phase was dilutedwith 100 ml of methylene chloride, dried over sodium sulfate,decolorized with activated carbon, filtered and evaporated to drynessunder reduced pressure to obtain 2.79 g of 2,3-dihydroxypropyl4-(m-benzoyl-phenyl)-2methyl-butyrate in the form of an orange oil.

Analysis: C₂₁ H₂₄ O₅ ; molecular weight = 356.40. Calculated: %C, 70.76;%H, 6.79. Found: %C, 70.5; %H, 6.7.

I.R. Spectrum: in accordance with structure.

Ester function: peak at 1733^(cm) ⁻¹.

Conjugated ketone: band at 1661 and 1653^(cm) ⁻¹.

Bands in aromatic region at 1601 and 1584^(cm) ⁻¹, hydroxyl band at 3601and 3494_(cm) ⁻¹.

EXAMPLE XI

A mixture of 4.39 g of 2,3-isopropylidenedioxypropyl4-(m-benzoyl-phenyl)-2-methyl-butyrate (Step B of Example IX), 44 ml ofethanol, 4.4 ml of water and 1.75 ml of concentrated potassium hydroxideaqueous solution was stirred at reflux for 1 hour and then wasevaporated to dryness under reduced pressure. The residue was dissolvedin 50 ml of water and the solution was treated with activated carbon,filtered, and acidified with agitation at 20° C to a pH of 1 by additionof 18 ml of 2N hydrochloric acid. The oil formed was extracted 3 timeswith 20 ml of methylene chloride and the methylene chloride phase waswashed twice with 20 ml of water until just neutral. The solution wasdried over sodium sulfate, decolorized with activated carbon, filteredand evaporated to dryness under reduced pressure to obtain 3.02 g of anorange oil. The oil was purified by chromatography over silica withelution with 80-20-0.3 mixture of methylene chloride-acetone-acetic acidand after treatment with activated carbon, filtration and evaporation todryness, 2.37 g of 4-(m-benzoyl-phenyl)-2-methyl-butyric acid wereobtained as an orange oil.

Analysis: C₁₈ H₂₈ O₃ ; molecular weight = 282.32. Calculated: %C, 76.57;%H, 6.43. Found: %C, 76.3; %H, 6.4.

I.R. Spectrum: Presence of acid at 1743 and 1710^(cm) ⁻¹, free hydroxylpeak at 3488^(cm) ⁻¹ and associated hydroxy; conjugated ketone peak at1660^(cm) ⁻¹, and bands at aromatic region at 1600 and 1582^(cm) ⁻¹.

RMN Spectrum:

CH₃ --CH-- signal at 70 and 76.5 Hz.

Methylene central in a chain: signals at 90 to 130 Hz.

Methylene α to phenyl and CH; signal at 130 to 185 Hz.

Aromatic protons: signal at 440 to 475 Hz.

Mobile hydrogen at 570 Hz

EXAMPLE XII

Step a: methyl 4-(m-benzoyl-phenyl)-2-methyl- 2-bromo-butanoate

0.2 ml of bromine was added in 10 minutes at room temperature to asuspension of 500 mg of 4-(m-benzoyl-phenyl)-2-methyl-butyric acid and0.17 ml of phosphorus bromide and the mixture was heated at 52° C for 18hours and was then cooled to 20° C. 0.8 ml of methanol were addedthereto over 15 minutes and the mixture was refluxed for 10 minutes andcooled to room temperature. A solution of 32 mg of sodium sulfite in 2.4ml of water was added to the reaction mixture which was then extractedwith methylene chloride. The organic phase was washed with water untilthe wash water was neutral, dried over sodium sulfate, treated withactivated carbon, filtered and evaporated to dryness under reducedpressure. The residue was chromatographed over silica gel and elutedwith a 50-50 methylene chloride-hexane mixture to obtain 326 mg ofmethyl 4-(m-benzoyl-phenyl)-2-methyl-2-bromo-butanoate in the form of anoil.

Analysis: C₁₉ H₁₉ BrO₃ ; molecular weight = 375.27. Calculated: %C,60.81; %H, 5.10; %Br, 21.30. Found: %C, 60.6; %H, 5.1; %Br, 21.6.

Step b: methyl 4-(m-benzoyl-phenyl)-2-methyl-2-butenoate

A mixture of 1.46 g of methyl4-(m-benzoyl-phenyl)-2-methyl-2-bromo-butanoate and 7.3 ml of quinolinewas heated at 160° C for 3 hours and after cooling to room temperature,73 ml of 2N hydrochloric acid were added thereto. The mixture wasextracted with methylene chloride and the organic phase was washed with2N hydrochloric acid, with aqueous saturated sodium bicarbonate solutionand then with water. The solution was dried over sodium sulfate, treatedwith activated carbon, filtered and evaporated to dryness under reducedpressure. The residue was chromatographed over magnesium silicate andeluted with methylene chloride to obtain 615 mg of methyl4-(m-benzoylphenyl)-2-methyl-2-butenoate in the form of an oil.

Analysis: C₁₉ H₁₈ O₃ ; molecular weight = 294.33. Calculated: %C, 77.53;%H, 6.16. Found: %C, 77.6; %H, 6.2.

Step c: 4-(m-benzoyl-phenyl)-2-methyl-2-butenoic acid

A mixture of 615 mg of methyl 4-(m-benzoyl-phenyl)-2-methyl-2-butenoate,6.2 ml of ethanol, 0.6 ml of water and 0.4 ml of a concentrated aqueoussolution of potassium hydroxide was refluxed for 1 hour and then wasevaporated to dryness under reduced pressure. The residue was taken upin water and the solution was treated with activated carbon, filteredand acidified to a pH of 1 with 2 N hydrochloric acid. The solution wasextracted with methylene chloride and the organic phase was washed withwater, dried over sodium sulfate, treated with activated carbon,filtered and evaporated to dryness under reduced pressure. The residuewas chromatographed over silica gel with 90-10 ether-methylene chlorideeluant to obtain 287 mg of 4-(m-benzoyl-phenyl)-2-methyl-2-butenoic acidin the form of an oil.

Analysis: C₁₈ H₁₆ O₃ ; molecular weight = 180.31. Calculated: %C, 77.12;%H, 5.75. Found: %C, 77.2; %H, 5.7.

EXAMPLE XIII

Step a: ethyl 3-(p-chlorobenzoyl)-benzyl malonate

A solution of 28 g of ethyl malonate in 28 ml of dimethylformamide wasadded to a suspension of 8.4 g of sodium hydride in 260 ml ofdimethylformamide at a temperature of 10° to 15° C and the temperaturewas allowed to return to room temperature. After evolution of 3.9 litersof hydrogen, the resulting solution was poured into a suspension of 52.5g of 3-bromomethyl-4'-chlorobenzophenone (French BSM No. 8440 M) in 400ml of dimethylformamide at 24° C. The mixture was stirred for 2 hoursand was then evaporated to dryness under reduced pressure. The residuewas taken up in 500 ml of water and 75 ml of isopropyl ether and theorganic phase was decanted. The aqueous phase was extracted withisopropyl ether and the combined organic phases were dried over sodiumsulfate, treated with activated carbon, filtered and evaporated todryness under reduced pressure. The residue was dissolved in 63 ml ofisopropyl ether with agitation, was iced and crystallization wasstarted. After being iced overnight, the mixture was vacuum filtered andthe precipitate was washed with isopropyl ether. The mother liquors wereevaporated to dryness to obtain 48.7 g of ethyl3-(p-chlorobenzoyl)-benzyl malonate which was used as is for the nextstep.

For analysis, 795 mg of the raw product were chromatographed over silicagel with elution with a 96-4 benzeneethyl acetate mixture which afterevaporation gave 450 mg of pure product.

Analysis: C₂₁ H₂₁ ClO₅ ; -- molecular weight = 388.85. Calculated: %C,64.87; %H, 5.44; %Cl, 9.12. Found: %C, 65.1-65.1; %H, 5.3-5.2; %Cl,10.1-10.2.

I.R. Spectrum (chloroform): Presence of conjugated ketone at 1661^(cm)⁻¹, of carbonyl at 1729 and 1745^(cm) ⁻¹ and of aromatic.

Step b: 3-(3'-p-chlorobenzoyl-phenyl)-propionic acid

A solution of 15.2 g of ethyl 3-(p-chlorobenzoyl)-benzyl malonate in 50ml of acetic acid was added to a solution of 50 ml of sulfuric acid and50 ml of water and the mixture was refluxed under a nitrogen atmospherefor 20 hours and then cooled to room temperature. The mixture was pouredinto water and then extracted with methylene chloride. The organic phasewas extracted with N sodium hydroxide and the alkaline phase was treatedwith activated carbon, filtered and acidified by addition at 10° C withstirring of 270 ml of N hydrochloric acid. The mixture was vacuulmfiltered and the precipitate was washed with water and dried underreduced pressure to obtain 3.11 g of3-(3'-p-chlorobenzyl-phenyl)-propionic acid which was used as is for thenext step.

For analysis, 5 g of the raw product were dissolved in 15 ml ofrefluxing acetone and the solution was filtered hot and then was icedfor 30 minutes and was vacuum filtered. The precipitate was washed withwater and dried under reduced pressure to obtain 3.2 g of the pureproduct melting at 140° C. The product occurred in the form of acolorless solid soluble in chloroform and methylene chloride andinsoluble in water.

Analysis: C₁₆ H₁₃ ClO₃ ; molecular weight = 288.74. Calculated: %C,66.56; %H, 4.54; %Cl, 12.28. Found: %C, 66.4; %H, 4.6; %Cl, 12.5.

I.R. Spectrum (chloroform): Presence of dimeric acid carbonyl at1712^(cm) ⁻¹, of ketone at 1661^(cm) ⁻¹ and of aromatic at 1601, 1586and 1484^(cm) ⁻¹.

Step c: 3-(4"-diazo-3"-oxo-butyl)-4'-chloro-benzophenone

6.96 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionic acid and 70 ml ofthionyl chloride were refluxed for 3 hours and then evaporated todryness. The residue was taken up in 100 ml of benzene and evaporated todryness to obtain 8.7 g of 3-(3'-p-chlorobenzoyl-phenyl)-propionylchloride which was used as is.

190 ml of a methylene chloride solution of 13.25 g/liter of diazomethanewas added to a solution of 8.7 g of the said acid chloride in 50 ml ofmethylene chloride cooled to 10° C and the mixture was stirred overnightat room temperature and then evaporated to dryness to obtain 8 g of3-(4"-diazo-3"-oxo-butyl)-4'-chloro-benzophenone which was used as isfor the next step.

Step d: 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-thenyl)-butyrate

7 ml of a solution of 1 g of silver benzoate in 12.6 ml of triethylaminewere added dropwise with stirring at room temperature to a solution of 8g of the said diazoketone in 50 ml of2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and after the evolution of460 ml of nitrogen, the mixture was poured into water and filtered. Theaqueous phase was extracted with isopropyl ether and the organic phasewas washed with water, dried over sodium sulfate, treated with activatedcarbon, filtered and evaporated to dryness. The residue waschromatographed over magnesium silicate and was eluted with a 50-50petroleum ether-mixture which upon evaporation of the eluant gave 5 g of2,3-isopropylidenedioxypropyl 4-(3'-p-chlorobenzoyl-phenyl)-butyrate.

For analysis, the residue was dissolved in 40 ml of isopropyl ether andthe solution was treated with activated carbon, filtered and evaporatedto dryness to obtain 3.78 g of pure product in the form of a yellow oilsoluble in chloroform and methylene chloride and insoluble in water.

Analysis: C₂₃ H₂₅ ClO₅ ; molecular weight = 416.90. Calculated: %C,66.26; %H, 6.05; %Cl, 8.50. Found: %C, 66.1; %H, 5.9; %Cl, 9.1-9.1.

EXAMPLE XIV

2.4 g of 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-phenyl)-butyrate (Example XIII), 12 ml ofmethoxyethanol and 3.5 g of boric acid was heated at 100° C for 23 hoursand the mixture was then iced and filtered. The filtrate was added towater with agitation and was extracted with ether. The ether phAse waswashed with an aqueous saturated sodium chloride solution and then 40 mlof methylene chloride were added thereto. The organic phase was driedover sodium sulfate, treated with activated carbon, filtered andevaporated to dryness under reduced pressure. The residue waschromatographed over magnesium silicate and eluted with ether. The elutewas evaporated to dryness and the residue was dissolved in 20 ml ofmethylene chloride. The solution was filtered and evaporated to drynessto obtain 1.1 g of 2,3-dihydroxypropyl4-(3'-p-chlorobenzoyl-phenyl)-butyrate in the form of a yellow oilsoluble in chloroform, acetone and ether and insoluble in water.

Analysis: C₂₀ H₂₁ ClO₅ ; molecular weight = 376.84. Calculated: %C,63,74; %H, 5.62; %Cl, 9.41. Found: %C, 63.9; %H, 5.8; %Cl, 9.8.

I.R. Spectrum (chloroform): Presence of ester carbonyl at 1729^(cm) ⁻¹,of conjugated ketone at 1658^(cm) ⁻¹, of aromatic at 1582^(cm) ⁻¹ and ofOH

EXAMPLE XV

A mixture of 3.9 g of 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-phenyl)-butyrate, 39 ml of ethanol, 3.9 ml ofwater and 1.5 ml of 12.5N potassium hydroxide was refluxed for 11/2hours and then was evaporated to dryness. The residue was dissolved in30 ml of water and the solution was treated with activated carbon andfiltered. The filtrate was acidified by addition of 12 ml of 2Nhydrochloric acid with agitation and the mixture was vacuum filtered.The precipitate was washed with water until the wash water was neutraland dried under reduced pressure. The residue was dissolved in 30 ml ofa saturated aqueous sodium bicarbonate solution and the solution wastreated with activated carbon, filtered and acidified by addition of 20ml of 2N hydrochloric acid. The mixture was vacuum filtered and theprecipitate was washed with water until the wash water was neutral anddried under reduced pressure. The residue was empasted with stirringwith 10 ml of isopropyl ether and the mixture stood for 1 hour. Theresidue was washed with isopropyl ether and dried under reducedpressure. The residue was chromatographed over silica gel and elutedwith a 50-50 chloroform-acetone mixture which was evaporated underreduced pressure to obtain 1.3 g of 4-(3'-p-chlorobenzoyl-phenyl)-butyric acid melting at 94° C. The productoccurred in the form of a colorless solid soluble in benzene, chloroformand acetone and insoluble in water.

Analysis: C₁₇ H₁₅ ClO₃ ; molecular weight = 302.77. Calculated: %C,67.44; %H, 4.99; %Cl, 11.71. Found: %C, 67.6; %H, 5.1; %Cl, 11.8.

I.R. Spectrum(chloroform): Presence of acid: dimeric carbonyl at1709^(cm) ⁻¹, of conjugated ketone at 1659^(cm) ⁻¹, and of aromatic at1600, 1586, 1568 and 1749^(cm) ⁻¹.

EXAMPLE XVI

Step a: 3-(3'-chloro-2'-oxo-propyl)-benzophenone

20 g of m-benzoyl-phenyl acetic acid (prepared by process of Frenchpatent No. 1,546,478) and 100 ml of thionyl chloride were refluxed for 3hours and then evaporated to dryness. Excess thionyl chloride wasremoved by entrainment with benzene to obtain 21.74 g ofm-benzoyl-phenyl-acetic acid chloride.

A solution of 21.74 g of the said acid chloride in 40 ml of methylenechloride was added to 570 ml of a solution of methylene chloridetitrating 18.7 g/liter of diazomethane at 5° C and the mixture wasstirred overnight to obtain a methylene chloride solution of3-(3'-diazo-2'-oxo-propyl)benzophenone. A current of hydrochloric gaswas passed through the said solution for 2 hours at room temperature andthe methylene chloride solution was washed with water, then with anaqueous saturated sodium bicarbonate solution and finally water. Thesaid solution was dried over sodium sulfate, treated with activatedcarbon, filtered and evaporated to dryness. The residue was dissolved in50 ml of methylene chloride and the solution was passed through amagnesium silicate column and evaporated to dryness. The residue wasempasted with 20 ml of isopropyl ether for 10 minutes and was vacuumfiltered, washed with isopropyl ether and dried under reduced pressureto obtain 17.31 g of 3-(3'-chloro-2'-oxo-propyl)-benzophenone which wasused as is for the next step.

For analysis, 840 mg of the residue were chromatographed over silica geland were eluted with a 25-75 ethyl ether-petroleum ether mixture whichwas evaporated to dryness. The residue was empasted with isopropyl etherand dried under reduced pressure to obtain 630 mg of pure productmelting at 64° C. The product was in the form of a colorless solidsoluble in chloroform and insoluble in water.

Analysis: C₁₆ H₁₃ ClO₂ ; molecular weight = 272.74. Calculated: %C,70.46; %H, 4.81; %Cl, 13.00. Found: %C, 70.3; %H, 4.8; %Cl, 13.0.

I.R. Spectrum (chloroform): Presence of CO at 1733^(cm) ⁻¹ and of CO andaromatic at 1661, 1601, 1588 and 1582^(cm) ⁻¹.

Step b: 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol

A solution of 11.23 g of 3'(3'-chloro-2'-oxo-propyl)-benzophenone in 112ml of isopropanol was added to 50 ml of isopropanol and 17 g of aluminumisopropylate heated to 50° C and the mixture was refluxed for 2 hourswhile slowly distilling isopropanol and the acetone formed while keepingthe volume constant by adding 30 ml of isopropanol. The mixture wasconcentrated to 50 ml and after returning to room temperature, themixture was added with stirring to a mixture of ice-water-hydrochlorideacide. The mixture was extracted with methylene chloride and the organicphase was washed with water, dried over sodium sulfate, treated withactivated carbon, filtered and evaporated to dryness to obtain 11.97 gof 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol which was used as is forthe next step.

For analysis, 1 g of the residue was chromatographed over magnesiumsilicate and was eluted with methylene chloride which as evaporated toobtain 242 mg of pure product melting at 65° C. The product was acolorless solid soluble in chloroform.

Analysis: C₁₆ H₁₇ ClO₂ ; molecular weight = 276.77. Calculated: %C,69.44; %H, 6.19; %Cl, 12.81. Found: %C, 69.3; %H, 6.3; %Cl, 13.0.

I.R. Spectrum (chloroform): Presence of OH at 3588^(cm) ⁻¹ and aromatic.

Step c: 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol

A mixture of 11.97 g of 3-(3'-chloro-2'-hydroxypropyl)-benzhydrol, 120ml of ethanol, 2.4 ml of water and 2.66 g of potassium cyanide wasrefluxed for 3 hours and then evaporated to dryness. The residue wastaken up in 200 ml of methylene chloride and the organic phase waswashed with water, dried over sodium sulfate, treated with activatedcarbon, filtered and evaporated to dryness. The residue waschromatographed over silica and was eluted with a 75-25 methylenechloride-ethyl acetate mixture which was evaporated to obtain 7.8 g of3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in the form of an orangeamorphous solid soluble in chloroform and insoluble in water.

Analysis: C₁₇ H₁₇ NO₂ ; molecular weight = 267.31. Calculated: %C,76.38; %H, 6.41; %N, 5.24. Found: %C, 76.2; %H, 6.3; %N, 4.9.

I.R. Spectrum (chloroform): Presence of C.tbd.N, free and associated OHand aromatic.

Step d: 3-(3'-cyano-2'-hydroxypropyl)-benzophenone k

7.35 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydrideper 100 ml was added with stirring at 0° C to 7.8 g of3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in 78 ml of acetone and themixture was allowed to stand at 0° C for 5 minutes and was then pouredinto water with stirring. The mixture was extracted with methylenechloride and the organic phase was washed with water, dried over sodiumsulfate, treated with activated carbon, filtered and evaporated todryness to obtain 7.4 g of 3-(3'-cyano-2'-hydroxypropyl)-benzophenonewhich was used as is for the next step.

I.R. Spectrum (chloroform): Presence of cyano at 2252^(cm) ⁻¹, of OH at3601^(cm) ⁻¹, of CO at 1660^(cm) ⁻¹ and of aromatic at 1600, 1584 and1482^(cm) ⁻¹.

Step e: ethyl 4-(m-benzoyl-phenyl)-3-hydroxy-butyrate

A current of hydrochloric acid gas was passed through a solution of 7.4g of 3-(3'-cyano-2'-hydroxypropyl)-benzophenone in 74 ml of ethanol for1 hour at room temperature and the mixture was refluxed for 1 hour andthen the ethanol was removed at 50° C. The residue was taken up in 200ml of methylene chloride and the organic phase was washed with water,then an aqueous sodium bicarbonate solution and finally with water. Thesolution was dried over sodium sulfate, treated with activated carbon,filtered and evaporated to dryness to obtain 7.62 g of ethyl4(-m-benzoyl-phenyl)-3-hydroxy-butyrate.

For analysis, the residue was chromatographed over silica and was elutedwith a 95-5 mixture of methylene chloride-acetone which was evaporatedto obtain 5.5 g of pure product in the form a yellow amorphous solidsoluble in chloroform and ethanol and insoluble in water.

Analysis: C₁₉ H₂₀ O₄ ; molecular weight = 312.35. Calculated: %C, 73.06;%H, 6.45. Found: %C, 72.8; %H, 6.3.

I.R. Spectrum (chloroform): Presence of aromatic at 1600, 1582 and1477^(cm) ⁻¹, of ester CO at 1721^(cm) ⁻¹, of conjugated ketone at 1660and 1652^(cm) ⁻¹ and of complex OH at 3590^(cm) ⁻¹. Absence of C.tbd.N.

EXAMPLE XVII

2.7 ml of water and 1.4 ml of 12.5N potassium hydroxide were added to asolution of 2.7 g of ethyl 4-(m-benzoylphenyl)-3-hydroxy-butyrate in 27ml of ethanol and the mixture was refluxed for 11/2 hours and thenevaporated to dryness. The residue as taken up in 27 ml of water and thesolution was treated with activated carbon, filtered and acidified to apH of 1 by adding 10 ml of 2N hydrochloric acid with stirring at 10° C.The mixture was extracted with methylene chloride and the organic phasewas washed with water, dried over sodium sulfate, treated with activatedcarbon, filtered and evaporated to dryness to obtain 2.36 g of4-(m-benzoyl-phenyl)-3-hydroxy-butyric acid in the form of a colorlessamorphous solid soluble in chloroform and insoluble in water.

Analysis: C₁₇ H₁₆ O₄ ; molecular weight = 284.30. Calculated: %C, 71.82;%H, 5.67. Found: %C, 71.6; %H, 5.8.

I.R. Spectrum (chloroform): Presence of OH at 3589^(cm) ⁻¹, of acid at1710^(cm) ⁻¹, of conjugated ketone at 1658^(cm) ⁻¹ and of aromatic at1601 and 1582^(cm) ⁻¹.

EXAMPLE XVIII

315 mg of phosphoric anhydride were added to a solution of 1.12 g ofethyl 4-(m-benzoyl-phenyl)-3-hydroxybutyrate in 20 ml of xylene and themixture was refluxed for 2 hours and then cooled to room temperature.The organic phase was washed with water, then with an aqueous saturatedsodium bicarbonate solution and then water, dried over sodium sulfate,treated with activated carbon, filtered and evaporated to dryness underreduced pressure. The residue was chromatographed over silica gel andwas eluted with methylene chloride which was evaporated to dryness toobtain ethyl 4-(m-benzoylphenyl)-3-butenoate whose ultraviolet spectrumwas in accord with the structure.

A mixture of 275 mg of ethyl 4-(m-benzoyl-phenyl)-3-butenoate, 2.75 mlof ethanol, 0.275 ml of ethanol, 0.275 ml of water and 0.08 ml of 12.5Npotassium hydroxide was refluxed for 30 minutes and then was evaporatedto dryness. The residue was dissolved in 10 ml of water and the solutionwas treated with activated carbon, and filtered. 3 ml of N hydrochloricacid were added thereto and the mixture was extracted with methylenechloride. The organic phase was washed with water, dried over sodiumsulfate, treated with activated carbon, filtered and evaporated todryness under reduced pressure to obtain 166 mg of4-(m-benzoyl-phenyl)-3-butenoic acid in the form of a yellow oil solublein chloroform and ethanol and insoluble in water.

Analysis: C₁₇ H₁₄ O₃ ; molecular weight = 266.28. Calculated: %C, 76.67;%H, 5.30. Found: %C, 76.4; %H, 5.6.

EXAMPLE XIX

Step a: 2-(m-benzoyl-phenyl)-propionic acid

1300 ml of a methylene chloride solution titrating 12.5 g/liter ofdiazomethane was added progressively at 10°-15° C to a solution of 50 gof m-benzoyl-phenyl acetic acid in 500 ml of methylene chloride andafter stirring for 15 minutes, excess diazomethane was destroyed by theaddition of acetic acid. The organic solution was washed with an aqueoussaturated sodium bicarbonate solution and then with water and evaporatedto dryness under reduced pressure to obtain 52.5 g of methylm-benzoyl-phenyl-acetate which was used as is for the α-alkylation step.

138 ml of a solution of 1.55N butyl lithium in hexane was introducedover 20 minutes at -40° C to a mixture of 775 ml of tetrahydrofuran, 775ml of hexamethyl phosphor-triamide and 21.5 ml of diethylamine and afterstirring for 20 minutes, a solution of 52.5 g of the above ester in 470ml of tetrahydrofuran was added over 20 minutes. Then, 38 ml of methyliodide were added thereto and the mixture was stirred for 30 minutes atabout -40° C and then was progressively returned to 20° C. The reactionmixture was poured into 3 liters of water-ice mixture and was stirredand extracted with isopropyl ether. The extracts were washed with waterand evaporated to dryness under reduced pressure to obtain methyl2-(m-benzoyl-phenyl)-propionate which was used as is for thesaponification.

A mixture of 57 g of the said methyl ester, 570 ml of ethanol, 57 ml ofwater and 29.5 ml of 14N potassium hydroxide was refluxed for 1 hour andthe ethanol was distilled under reduced pressure. The residue asdissolved in 600 ml of water and the solution was acidified to a pH of 1by addition of concentrated hydrochloric acid. The mixture was extractedwith methylene chloride and the extracts were washed with water andevaporated to dryness under reduced pressure. The residue wascrystallized from isopropyl ether to obtain 31.2 g of2-(m-benzoyl-phenyl)-propionic acid melting at 82°-83° C.

Analysis: C₁₆ H₁₄ O₃ ; molecular weight = 254.27. Calculated: %C, 75.57;%H, 5.55. Found: %C, 75.3; %H, 5.7.

The IR and RMN spectra were in accord with the structure.

Step b: 3-(1'-methyl-2'-oxo-3'-chloropropyl)-benzophenone

Using the procedure of Step A of Example XVI,2-(m-benzoyl-phenyl)-propionic acid was converted into its acidchloride, then 3-(1'-methyl-2'-oxo-3'-diazopropyl)-benzophenone andfinally 3-(1'-methyl-2'-oxo-3'-chloropropyl)-benzophenone which waspurified by chromatography over silica gel and was eluted with methylenechloride to obtain the product melting at 60° C.

Microanalysis: C₁₇ H₁₅ ClO₂ ; molecular weight = 286.76. Calculated: %C,71.20; %H, 5.27; %Cl, 12.36. Found: %C, 71.5; %H, 5.6, %Cl, 12.4.

Step c: 3-(1'-methyl-2'-hydroxy-3'-chloropropyl)-benzhydrol

Using the procedure of Step B of Example XVI,3-(1'-methyl-2'-oxo-3'-chloropropyl)-benzophenone was reacted to form3-(1'-methyl-2'-hydroxy-3'-chloropropyl)-benzhydrol which was used as isfor the next step. For analysis, a portion of the raw product waschromatographed over silica gel to obtain an oil soluble in methylenechloride, chloroform and alcohols.

Analysis: C₁₇ H₁₉ ClO₂ ; molecular weight = 290.78. Calculated: %C,70.22; %H, 6.58; %Cl, 12.19. Found: %C, 70.1; 6.6; %Cl, 12.1.

Step d:

using the procedure of Step C of Example XVI,3-(1'-methyl-2'-hydroxy-3-chloropropyl)-benzhydrol was reacted to form3-(1'-methyl-2'-hydroxy-3'-cyanopropyl)-benzhydrol.

Analysis: C₁₈ H₁₉ NO₂ ; molecular weight = 281.35. Calculated: %C,76.84; %H, 6.81; %N, 4.98. Found: %C, 76.7; %H, 6.8; %N, 4.6.

Step e:

using the procedure of step D of Example XVI,3-(1'-methyl-2'-hydroxy-3'-cyanopropyl)-benzhydrol was reacted to form3-(1'-methyl-2'-hydroxy-3'-cyanopropyl)-benzophenone melting at 130° C.

Analysis: C₁₈ H₁₇ NO₂ ; molecular weight = 279.34. Calculated: %C,77.39; %H, 6.13; %N, 5.01. Found: %C, 77.5; %H, 6.3; %N, 5.2.

Step f:

using the process of Step E of Example XVI,3-(1'-methyl-2'-hydroxy-3'-cyanopropyl)-benzophenone was reacted to formethyl 4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyrate in the form of anoil soluble in chloroform, methylene chloride and alcohols.

Analysis: C₂₀ H₂₂ O₄ ; molecular weight = 326.39. Calculated: %C, 73.60;%H, 6.79. Found: %C, 73.8; %H, 7.0.

I.R. Spectrum (chloroform): Ester carbonyl at 1725^(cm) ⁻¹, conjugatedketone at 1661^(cm) ⁻¹, and aromatic at 1601, 1573 and 1473^(cm) ⁻¹.Absence of C.tbd.N.

EXAMPLE XX

A mixture of 818 mg of ethyl4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyrate, 8 ml of ethanol, 0.8ml of water and 0.2 ml of 14N potassium hydroxide was refluxed for 11/2hours and then was evaporated to dryness under reduced pressure. Theresidue was taken up in 20 ml of water and the solution was acidified toa pH of 1 by progressive addition of a 1N hydrochloric acid solution andwas then extracted with methylene chloride. The organic phase was washedwith water and evaporated to dryness under reduced pressure to obtain4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyric acid in the form of aproduct soluble in alcohols, methylene chloride and chloroform.

Analysis: C₁₈ H₁₈ O₄ ; molecular weight = 298.34. Calculated: %C, 72.46%H, 6.08. Found: %C, 72.3 %H, 6.0.

I.R. Spectrum (chloroform): Acid carbonyl at 1718^(cm) ⁻¹, acid OH at3494^(cm) ⁻¹, OH at 3575^(cm) ⁻¹ aromatic at 1601, 1582 and 1482^(cm) ⁻¹and CO at 1658^(cm) ⁻¹.

EXAMPLE XXI

Step a: 3-(2'-ethoxy carbonyl-3'-oxo-butyl)-benzophenone

Dry sodium ethylate prepared from 2.51 g of sodium was added to 125 mlof anhydrous benzene and 13.5 ml of ethyl acetylacetate at 20° C andafter heating at 100° C for 15 minutes, 27.5 g of3-bromomethyl-benzophenone were added all at once. The reaction mixturewas refluxed for 3 hours and after cooling to 20° C, the benzenesolution was washed twice with 25 ml of 2N hydrochloric acid and thenwith water until the wash water was neutral. The solution was dried oversodium sulfate and evaporated to dryness under reduced pressure toobtain 33.8 g of raw product which was chromatographed over silica geland was eluted with a 50-50 mixture of ether-petroleum ether (B.P. of40°-60° C) to obtain 15.3 g of3-(2'-oxo-3'-ethoxycarbonyl-butyl)-benzophenone in the form of a marronresin which was used as is for the next step.

Step b: 3-(3'-oxo-butyl)-benzophenone

A mixture of 14.2 g of 3-(2'-oxo-3'-ethoxycarbonylbutyl)-benzophenoneand 142 ml of 6N hydrochloric acid was refluxed with stirring of 17hours and after cooling to 20° C, the mixture was diluted with 140 ml ofwater and extracted 3 times with 50 ml of methylene chloride. Theorganic phase was washed with 50 ml of an aqueous saturated sodiumbicarbonate solution and twice with 50 ml of water, dried over sodiumsulfate and evaporated to dryness under reduced pressure to obtain 10.76g of 3-(3'-oxo-butyl)-benzophenone which was utilized as is for the nextstep.

Step c: 4-(m-benzoyl-phenyl)-butyric acid

A mixture of 3.15 g of product of Step B, 400 mg of sulfur, 2.5 ml ofmorpholine and 50 mgof p-toluene sulfonic acis was refluxed for 3 hoursand after cooling to room temperature, a mixture of 75 ml of aceticacid, 25 ml of sulfuric acid and 15 ml of water was added thereto. Themixture was refluxed for 15 hours, cooled to 20° C and added to water.The mixture was extracted with methylene chloride and the extracts wereevaporated to dryness. The residue was purified by crystallization fromisopropyl ether to obtain 4-(m-benzoyl-phenyl)-butyric acid, identicalto the product of Example I.

EXAMPLE XXII

A solution of 6.2 g of ethyl4-(m-benzoyl-phenyl)-4-methyl-3-hydroxy-butyrate (by process of Step Eof Example XIX) in 60 ml of pyridine was heated at 100° C for 3 hours inthe presence of 5 ml of phosphorus oxychloride and was then poured intoa mixture of 200 g of ice and 65 ml of concentrated hydrochloric acid.The mixture was extracted with ether and the ether phase was washed withwater, then with an aqueous saturated sodium bicarbonate solution andthen water until the wash water was neutral. The solution was dried oversodium sulfate, treated with activated carbon, filtered and evaporatedto dryness under reduced pressure to obtain 5.35 g of ethyl4-(m-benzoyl-phenyl)-4-methyl-3-butenoate.

A mixture of 5.35 g of the said ester in 50 ml of methanol and 20 ml of2N sodium hydroxide were refluxed for 2 hours and then the methanol wasdistilled off. The mixture was added to water, treated with activatedcarbon and filtered. The filtrate was acidified with 3 ml ofconcentrated hydrochloric acid and was extracted with ether. The etherextract was washed with water until the wash water was neutral, driedover sodium sulfate and evaporated to dryness under reduced pressure toobtain 4.31 g of 4-(m-benzoyl-phenyl)-4-methyl-3-butenoic acid.

EXAMPLE XXIII

Hydrogen was bubbled through a mixture of 2.2 g of4-(m-benzoyl-phenyl)-4-methyl-3-butenoic acid and 22 ml of ethanol inthe presence of 2.2 g of Raney nickel and after filtering, the mixturewas evaporated to dryness under reduced pressure. The residue was takenup in ether and the solution was extracted with dilute sodium hydroxide.The aqueous phase was treated with hydrochloric acid and was extractedwith ether. The ether phase was washed with water, dried over sodiumsulfate, treated with activated carbon, filtered and evaporated todryness under reduced pressure to obtain 1.96 g of4-(m-benzoyl-phenyl)-4-methyl-butyric acid in the form of an amorphousproduct.

EXAMPLE XXIV

Step a: 2-methyl-3-nitro-4'-fluorobenzophenone

150 g of aluminum chloride were added over 30 minutes at 40° C under anargon atmosphere to a suspension of 107.8 g of 2-methyl-3-nitro-benzoylchloride (Step A -- Example IV) in 450 ml of fluorobenzene and themixture was held at this temperature for 41 hours. After icing, themixture was added to 1 liter of ice water and 250 ml of concentratedhydrochloric acid and after stirring for 30 minutes, the mixture wasextracted with methylene chloride. The extract was washed with water,then with N sodium hydroxide and then with water until the wash waterwas neutral. The solution was dried over magnesium sulfate, treated withactivated carbon, filtered and evaporated to dryness under reducedpressure to obtain 115.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone inthe form of white crystals. For analysis, a sample of the product wascrystallized from n-pentane and had a melting point of 64° C.

Analysis: C₁₄ H₁₀ FNO₃ ; molecular weight = 259.64. Calculated: %C,64.86; %H, 3.89; %F, 7.33; %N, 5.40. Found: %C, 65.0; %H, 3.8; %F, 7.4;%N, 5.6.

Step b: 2-methyl-3-amino-4'-fluorobenzophenone-hydrochloride

38 ml of hydrochloric acid, 23 g of activated carbon and 12 ml of asolution of 20% palladium chloride in water were added to a solution of114.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone in 1 liter of ethanoland then a current of hydrogen was passed therethrough for 3 hours. Thereaction mixture was filtered and the filter was rinsed with ethanol.The filtrate was concentrated until crystallization began and was icedand then vacuum filtered. The precipitate was empasted with ethanol anddried under reduced pressure to obtain 59.5 g of2-methyl-3-amino-4'-fluorobenzophenone in the form of white crystalsmelting at 170° C. Evaporation of the mother liquor and treatment withisopropyl ether gave another 50.5 g of product for a total of 110 g. Foranalysis, a sample of the product was crystallized from an aqueoussolution of 5% hydrochloric acid and melted at 170° C.

Analysis: C₁₄ H₁₃ ClFNO; molecular weight = 265.72. Calculated: %C,63.28; %H, 4.93; %Cl, 13.34; %F, 7.15; %N, 5.27. Found: %C, 63.6; %H,5.1; %Cl, 13.3; %F, 7.0; %N, 5.3.

Step c: 1-chloro-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2

30 ml of hydrochloric acid were added at 5° C to a suspension of 26.57 gof 2-methyl-3-amino-4'-fluorobenzophenone hydrochloride in 250 ml ofwater and then 7.5 g of sodium nitrite were added thereto with stirringto obtain a solution of 2-methyl-4'-fluorobenzophenone-3-diazoniumchloride.

A solution of 60 g of sodium acetate, 5 g of cuprous chloride in 25 mlof water and 150 ml of acetone was cooled to -10° C and then 140 ml of1,3-butadiene followed by the above solution of the diazonium chloridewere added thereto. The temperature was returned to room temperature andthe pH of the mixture was adjusted to 4 by addition of sodium acetate.The mixture was extracted with ether and the ether phase was washed withwater, then with N sodium hydroxide and with water until the wash waterwas neutral. The ether phase was dried over magnesium sulfate, treatedwith activated carbon, filtered and evaporated to dryness bydistillation under reduced pressure. The residue was chromatographedover silica gel and was eluted with methylene chloride which wasevaporated to obtain 13.70 g of1-chloro-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2. The productwas crystallized from refluxing pentane for analysis and melted at 67°C.

Analysis: C₁₈ H₁₆ ClFO; molecular weight = 302.78. Calculated: %C,71.40; %H, 5.33; %Cl, 11.71; %F, 6.28. Found: %C, 71.2; %H, 5.3; %Cl,11.8; %F, 6.3.

Step d: 1-acetoxy-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2

A solution of 6 g of1-chloro-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2 and 6 g ofpotassium acetate in 60 ml of acetic acid was refluxed for 23 hours, andafter cooling to room temperature, the mixture was added to water andextracted with ether. The ether extract was washed with water, with anaqueous saturated sodium bicarbonate solution and then with water untilthe wash water was neutral. The ether phase was dried over magnesiumsulfate, treated with activated carbon, filtered and evaporated todryness by distillation under reduced pressure. The residue waschromatographed over silica gel and was eluted with methylene chloridewhich was evaporated to obtain 5.96 g of1-acetoxy-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2 in the formof a yellow oil.

Analysis: C₂₀ H₁₉ FO₃ ; molecular weight = 326.37. Calculated: %C,73.60; %H, 5.87; %F, 5.82. Found: %C, 73.6; %H, 5.9; %F, 5.9.

Step e: 1-hydroxy-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl) butene-2

A solution of 6.01 g of1-acetoxy-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2 in 30 ml ofmethanol and 30 ml of 2N sodium hydroxide was heated at 60° C for 1 hourand after eliminating the methanol by distillation, the mixture wasextracted with ether. The ether phase was washed with water until thewash water was neutral, dried over magnesium sulfate, treated withactivated carbon, filtered and evaporated to dryness under reducedpressure to obtain 5.15 g of1-hydroxy-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2 in the formof a yellow oil.

Analysis: C₁₈ H₁₇ FO₂ ; molecular weight = 284.33. Calculated: %C,76.04; %H, 6.03; %F, 6.68. Found: %C, 76.2; %H, 6.3; %F, 6.5.

Step f: 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butanol

A current of hydrogen was bubbled for 2 hours through a solution of 4.97g of 1-hydroxy-4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butene-2 in 50 mlof methanol containing 5 g of Raney nickel and the mixture was thenfiltered. The filtrate was evaporated to dryness under reduced pressureand the residue was taken up in methylene chloride. The organic solutionwas dried over magnesium sulfate, treated with activated carbon andevaporated to dryness by distillation under reduced pressure. Theresidue was chromatographed over silica gel and was eluted with an 8-2methylene chloride acetone mixture to obtain 4.2 g of4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butanol in the form of acolorless oil.

Analysis: C₁₈ H₁₉ FO₂ ; molecular weight = 286.35. Calculated: %C,75.50; %H, 6.69; %F, 6.63. Found: %C, 75.3; %H, 6.8; %F, 5.7.

Step g: 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butyric acid

14 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydrideper 100 ml were added over 25 minutes at 10° C to a solution of 3.47 gof 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butanol in 35 ml of acetoneand after returning the mixture to room temperature, the mixture wasstirred overnight. The mixture was poured into ice water and vacuumfiltered, was washed with water until the wash water was neutral and theprecipitate recovered was dried over phosphoric acid and crystallizedfrom cycloxane to obtain 3.02 g of4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butyric acid in the form ofcolorless crystals melting at 94° C.

Analysis: C₁₈ H₁₇ FO₃ ; molecular weight = 300.33. Calculated: %C,71.99; %H, 5.70; %F, 6.33. Found: %C, 72.1; %H, 5.9; %F, 6.0.

EXAMPLE XXV

Using the process of Step C of Example XXIV,2-methyl-3-amino-4'-chlorobenzophenone (Step B of Example IV) wasreacted to successively obtain2-methyl-4'-chlorobenzophenone-3-diazonium chloride and then1-chloro-4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butene-2.

The latter product was reacted by the process of Step D of Example XXIVto obtain 1-acetoxy-4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butene-2which was treated by the process of Step E of Example XXIV to obtain1-hydroxy-4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butene-2.

The latter product was oxidized with chromic anhydride to obtain4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butene-2-oic acid in the form ofcolorless crystals melting at 136° C.

Analysis: C₁₈ H₁₅ ClO₃ ; molecular weight = 314.77. Calculated: %C,68.69; %H, 4.80; %Cl, 11.26. Found: %C, 68.7; %H, 4.9; %Cl, 11.5.

EXAMPLE XXVI

Step a: 2-methoxy-3-methyl-4'-chlorobenzophenone

A solution of 195.9 g of 2-hydroxy-3-methyl-4'-chlorobenzophenone[Huston et al., JACS, Vol. 73, (1951), p. 2483] in 1 liter ofdimethylformamide was added with stirring to a suspension of 40.8 g ofsodium hydride in 200 ml of dimethylformamide and the mixture wasstirred for 1 hour with cooling in an ice-water bath. Then, a solutionof 170.4 g of methyl iodide in 800 ml of dimethylformamide was addedthereto over 40 minutes and the mixture was then stirred for 16 hours inthe ice-water bath. The mixture was filtered to remove insolubles andthe filtrate was treated with activated carbon, filtered and wasevaporated to dryness under reduced pressure. The residue was taken upin 1 liter of ether and 200 ml of water and the aqueous phase wasreextracted with ether. The combined ether phases were washed withwater, dried over magnesium sulfate, treated with activated carbon,filtered and evaporated to dryness. The residue was chromatographed oversilica and was eluted with methylene chloride to obtain 171 g of2-methoxy-3-methyl-4'-chlorobenzophenone in the form of colorlesscrystals melting at 43° C.

Analysis: C₁₅ H₁₃ ClO₂ ; molecular weight = 260.72. Calculated: %C,69.10; %H, 5.03; %Cl, 13.60. Found: %C, 69.1; %H, 5.1; %Cl, 13.8.

Step b: 2-methoxy-3-bromomethyl-4'-chlorobenzophenone

A mixture of 1.78 g of N-bromo-succinimide and 10 mg of benzoyl peroxidewas added to a suspension of 2.6 g of2-methoxy-3-methyl-4'-chlorobenzophenone in 15 ml of carbontetrachloride and the solution was refluxed for 4 hours. The insolubleswere removed by filtration and the filtrate was evaporated to dryness toobtain 3.32 g of 2-methoxy-3-bromomethyl-4'-chlorobenzophenone in theform of a clear yellow oil.

Analysis: C₁₅ H₁₂ BrClO₂ ; molecular weight = 339.62. Calculated: %C,53.05; %H, 3.56; %Br, 23.53; %Cl, 10.44. Found: %C, 52.9; %H, 3.6; %Br,23.7; %Cl, 10.2.

Step c: ethyl 2-methoxy-3-(p-chlorobenzoyl)-benzyl malonate

A solution of 108.4 g of ethyl malonate in 450 ml of dimethylformamidewas added at 10° C to a suspension of 32.6 g of sodium hydride in 300 mlof dimethylformamide and the solution was held at 10° C until gasevolution ceased. Then, a solution of 202.1 g of2-methoxy-3-bromomethyl-4'-chlorobenzophenone in 800 ml ofdimethylformamide was slowly added thereto and after standing overnightat room temperature, the solution was treated with activated carbon,filtered and evaporated to dryness under reduced pressure. The residuewas taken up in ether and then water. The aqueous phase was extractedwith ether and the combined ether phases were washed with water, driedover magnesium sulfate, treated with activated carbon, filtered andevaporated to dryness under reduced pressure to obtain 237.6 g of ethyl2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonate in the form of an oil.

Analysis: C₂₂ H₂₃ ClO₆ ; molecular weight = 418.88. Calculated: %C,63.08; %H, 5.53; %Cl, 8.46. Found: %C, 62.9; %H, 5.5; %Cl, 8.7.

Step d: 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonic acid

A solution of 86.4 g of sodium hydroxide in 180 ml of water was addedwith stirring to a suspension of 226.6 g of ethyl2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonate in 2.8 liters of methanoland the mixture was refluxed for 3 hours and then was cooled to roomtemperature. The mixture was filtered and the precipitate recovered waswashed with methanol, then with ether and dried. The residue wasdissolved in 800 ml of water and the solution was washed with ether andacidified to a pH of 1 by addition of 0.5N hydrochloric acid. The acidprecipitate formed was extracted with ether and the combined organicphases were washed with water, dried over magnesium sulfate, treatedwith activated carbon, filtered and evaporated to dryness under reducedpressure. The residue was crystallized from benzene to obtain 96.2 g of2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonic acid in the form ofcolorless crystals which melted at 142° C after crystallization frombenzene.

Analysis: C₁₈ H₁₅ ClO₆ ; molecular weight = 362.77. Calculated: %C,59.60; %H, 4.16; %Cl, 9.77. Found: %C, 59.7; %H, 4.2; %Cl, 9.8.

Step e: 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid

96.2 g of 2-methoxy-3-(p-chlorobenzoyl)-benzylmalonic acid were heatedat 170°-195° C under an argon atmosphere and after the evolution ofcarbon dioxide gas, the mixture was cooled and added to 1 liter ofether. The acid mixture was extracted several times with 600 ml of asolution of 10% potassium carbonate and 150 ml of water. The combinedaqueous phases were acidified with concentrated hydrochloric acid andthe acid precipitate formed was extracted with ether. The combined etherphases were washed with water, dried over magnesium sulfate andevaporated to dryness under reduced pressure. The residue wascrystallized from cyclohexane to obtain 56.8 g of3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid in the form ofcolorless crystals.

Analysis: C₁₇ H₁₅ C10₄ ; molecular weight = 318.77. Calculated: %C,64.06; %H, 4.74; %Cl, 11.12. Found: %C, 64.0; %H, 4.7; %Cl, 11.1.

Step f: 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionyl chloride

A solution of 5.1 g of3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid in 25 ml ofthionyl chloride was refluxed for 21/2 hours and the excess thionylchloride was distilled off. The residue was taken up in benzene and wasevaporated to dryness to obtain 5.6 g of3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionyl chloride which wasused as is for the next step.

Step g: 2-methoxy-3-(4"-diazo-3"-oxo-butyl)-4'-chlorobenzophenone

112 ml of methylene chloride titrating 15.1 g/l liter of diazomethanewere added to a solution of 5.6 g of the acid chloride from Step F in 40ml of methylene chloride cooled to 0° C and the mixture was stirredovernight at room temperature then evaporated to dryness to obtain 6.1 gof 2-methoxy-3-(4"-diazo-3"-oxo-butyl)-4'-chlorobenzophenone which wasused as is for the next step.

Step h: 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-butyrate

2.5 ml of a solution of 1 g of silver benzoate in 12.5 ml oftriethylamine were added dropwise with stirring to a solution of 6.1 gof the product of Step G in 35 ml of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane at room temperature and after the evolution ofnitrogen ceased, the reaction mixture was poured into water andextracted with ether. The combined organic phases were washed with waterand evaporated to dryness by distillation of ether. The residue waschromatographed over silica gel and was eluted with a 7-3 mixture ofbenzene-ethyl acetate to obtain 4.25 g of 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-butyrate in the form of acolorless oil.

Analysis: C₂₄ H₂₇ C10₆ ; molecular weight = 446.905. Calculated: %C,64.49; %H, 6.09; %Cl, 7.93. Found: %C, 64.7; %H, 5.9; %Cl, 8.2.

EXAMPLE XXVII

A mixture of 4.46 g of 2,3-isopropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methhoxy-phenyl)-butyrate (Example XXVI), 6.18g of boric acid and 25 ml of methoxy ethanol was heated at 100° C for 2hours and after cooling, the mixture was poured into water and extractedwith ether. The combined ether phases were washed with water, dried overmagnesium sulfate, treated with activated carbon, filtered andevaporated to dryness under reduced pressure. The residue waschromatographed over silica gel and was eluted with a 1-1 methylenechloride - acetone mixture to obtain 3.65 g of 2,3-dihydroxypropyl4-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-butyrate in the form of ayellow oil.

Analysis: C₂₁ H₂₃ C10₆ ; molecular weight = 406.87. Calculated: %C,61.99; %H, 5.70; %Cl, 8.71. Found: %C, 61.8; %H, 6.0; %Cl, 8.5.

EXAMPLE XXVIII

2,3-ispropylidenedioxypropyl4-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-butyrate (Example XXVI) wassaponified to obtain 4-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-butyricacid.

PHARMACOLOGICAL STUDY A. Anti-inflammatory Activity

The test used was that of Branceni, et al, slightly modified [Arch. Int.Pharmacodyn, Vol. 152 (1954), p. 15 ] and consisted of administering torats weighing about 150 g a single injection of 1 mg ofnaphthoyheparamine (N.H.A.) into the plantain aponeurosus of the rearpaw, the said injection provoking the formation of inflammatory edema.The products to be tested were orally administered in aqueous solutionor suspension one hour before the irritant injection. The inflammationwas measured by plethysmometry with an electric plethysmometer with thevolume of the paw being measured immediately before and 2 hours afterthe irritant injection. The increase in paw volume between the twomeasurements represents the degree of inflammation and the averagedegree in each group of animals is expressed in absolute values and apercentage of the control animals.

Under these conditions, the standard active dose more accuratelycalculated for a product is the DA₄₀, the dose that diminishes thedegree of inflammation by 40% of that of the controls. The products wereadministered at different doses and the results are reported in thefollowing Tables.

    __________________________________________________________________________                     Dose                        DA.sub.40                                         Administered                                                                         Increase of paw volume                                                                             in                               Products     Lots                                                                              in mg/kg                                                                             in 2 hours  % of Protection                                                                        mg/kg                            __________________________________________________________________________    4-(m-benzoyl-phenyl)-                                                                     Controls                                                                           0      17.1        --                                        butyric acid                                                                              Product                                                                            50      4.6        73                                                    Controls                                                                           0      18.6        --        5                                           Product                                                                            5      11.4        39                                                         10      5.8        69                                        2,3-isopropylidene-                                                                       Controls                                                                           0      28.6        --                                        dioxypropyl 4-(3'-p-                                                          chlorobenzoyl-2'-                                                                         Product                                                                            1      20.1        30                                        methyl-phenyl-buty-                                                           rate        Controls                                                                           0      32.1        --       2.5                                          Product                                                                            0.5    24.8        23                                                         2      25.3        22                                                    Controls                                                                           0      21.3        --                                                    Product                                                                            4      11.0        48                                                         8       7.1        67                                        2,3-isopropylidene-                                                                       Controls                                                                           0      31.3        --                                        dioxypropyl 4-(3'-p-                                                          chlorobenzoyl-phenyl)                                                                     Product                                                                            5      11.6        63                                        butyrate                                                                                  Controls                                                                           0      22.3        --        3                                           Product                                                                            1      16.6        26                                                         2.5    14.8        34                                        2,3-dihydroxypropyl                                                                       Controls                                                                           0      32.1        --                                        4-(3'-p-chlorobenzoyl                                                         2'-methyl-phenyl)-                                                                        Product                                                                            5      22.8        29                                        butyrate                                                                                  Controls                                                                           0      24.3        --                                                    Product                                                                            10     11.4        53                                                         20      9.9        59        5                                           Controls                                                                           0      26.6        --                                                    Product                                                                            2.5    15.8        41                                                    Controls                                                                           0      26.8        --                                                    Product                                                                            2.5    20.6        23                                                         5      14.3        46                                        2,3-dihydroxypropyl                                                                       Controls                                                                           0      17.6        --                                        4-(m-benzoyl-phenyl)                                                          butyrate    Product                                                                            5      10.9        38                                                    Controls                                                                           0      24.5        --        8                                           Product                                                                            2.5    19.5        20                                                         10     15.1        38                                                    Controls                                                                           0      13.6        --                                                    Products                                                                           25      5.4        61                                        2,3-dihydroxypropyl                                                                       Controls                                                                           0      24.0        --                                        4-(3'-p-chlorobenzoyl)                                                        phenyl)-butyrate                                                                          Product                                                                            5      19.3        20                                                    Controls                                                                           0      22.1        --        9                                           Product                                                                            10     12.0        46                                        4-(m-benzoyl-phenyl)-                                                                     Controls                                                                           0      27.0        --                                        3-hydroxy-butyric acid                                                                    Product                                                                            10     18.1        33                                                    Controls                                                                           0      13.6        --       17                                           Product                                                                            25      8.4        39                                        Ethyl 4-(m-benzoyl-                                                                       Controls                                                                           0      20.8        --                                        phenyl)-3-hydroxy-                                                            butyrate    Product                                                                            10     15.3        26                                                    Controls                                                                           0      13.6        --       15                                           Product                                                                            25      5.8        58                                                         50      4.4        65                                        2,3-isopropylidene-                                                                       Controls                                                                           0      27.0        --                                        dioxypropyl 4-(m-                                                             benzoyl-phenyl)-                                                                          Product                                                                            10     23.4        13                                        butyrate                                                                                  Controls                                                                           0      13.6        --       15                                           Product                                                                            25      5.1        62                                                         50      2.5        82                                        4-(m-benzoyl-phenyl)                                                                      Controls                                                                           0      17.3        --                                        2-methyl-butyric acid                                                                     Product                                                                            10     14.8        15                                                    Controls                                                                           0      21.5        --       35                                           Product                                                                            50     11.0        49                                                         100     9.5        56                                        4-(3'-p-chlorobenzoyl                                                                     Controls                                                                           0      24.3        --                                        2'-methyl-phenyl)-                                                            butyric acid                                                                              Product                                                                            10     22.0         9                                                         20     12.1        50                                                    Controls                                                                           0      29.1        --       19                                           Product                                                                            5      26.3        10                                                         10     21.8        25                                        4-(3'-p-chlorobenzoyl                                                                     Controls                                                                           0      22.4        --                                        phenyl)-butyric acid                                                                      Product                                                                            10     19.9        11                                                    Controls                                                                           0      30.3        --       25                                           Product                                                                            20     18.6        39                                                    Controls                                                                           0      20.6        --                                                    Product                                                                            50     11.5        44                                        2,3-isopropylidene-                                                                       Controls                                                                           0      22.0        --                                        dioxypropyl 4-(m-ben-                                                         zoyl-phenyl)-2-methyl-                                                                    Product                                                                            10     16.6        25                                        butyrate                                                                                  Controls                                                                           0      17.3        --       30                                           Product                                                                            20     14.6        16                                        2,3-isopropylidene-                                                                       Controls                                                                           0      21.6        --                                        dioxypropyl 4-(m-ben-                                                         zoyl-phenyl)-2-methyl-                                                                    Product                                                                            50     10.4        52                                        butyrate                                                                      2,3-dihydroxypropyl                                                                       Controls                                                                           0      22.0        --                                        4-(m-benzoyl-phenyl)                                                          2-methyl-butyrate                                                                         Product                                                                            10     16.0        27       40                                           Controls                                                                           0      17.3        --                                                    Product                                                                            20     11.8        32       40                                           Controls                                                                           0      23.9        --                                                    Product                                                                            40     13.9        42                                                         50     12.6        47                                        __________________________________________________________________________

B. Analgesic Effect

The test used was based on the fact noted by R. Koster et al (Fed.Proc., (1959) Vol. 18, p. 412) wherein the intraperitoneal injection ofacetic acid causes in mice characteristic repeated stretching andtwisting movements which can persist for more than 6 hours. Analgesicsprevent or suppress this syndrome which, therefore, can be considered asexternalization of a diffuse abdominal pain.

A solution of 0.6% acetic acid in water containing 10% arabic gum wasused and the dose which release the syndrome under these conditions was0.01 cc/gm, that is 60 mg/kg of acetic acid. The test compounds wereadministered orally one-half hour before the intraperitoneal injectionof acetic acid, the mice having fasted since the night before theexperiment. For each dose and for each control, which are obligatory foreach test, a group of 5 animals was used. For each mouse, thestretchings were observed and counted and then added for the group of 5during a period of 15 minutes starting immediately after the injectionof acetic acid.

The following Table summarizes the results.

    ______________________________________                                        Products      % of Protection                                                 Doses administered                              DA.sub.50                     in mg/kg      2     5     10  20  50  100  200  mg/kg                         ______________________________________                                        4-(m-benzoyl-phenyl)                                                                              45    60  51  77            10                            butyric acid                                                                  2,3-isopropylidene-                             10                            dioxypropyl 4-(3'-p-                            to                            chlorobenzoyl-2'-   32    53  53  64            20                            methyl-phenyl)-buty-                                                          rate                                                                          2,3-isopropylidene-                                                           dioxypropyl 4-(3'-p-                                                                              23    27  62  72            15                            chlorobenzoyl-phenyl)                                                         butyrate                                                                      2,3-dihydroxypropyl                                                           4-(3'-p-chlorobenzoyl-                                                                            32    62  62  70            10                            2'-methyl-phenyl)-                                                            butyrate                                                                      2,3-dihydroxypropyl                                                           4-(m-benzoyl-phenyl)-                                                                       28    21    51  42  61  78        10                            butyrate                                                                      2,3-dihydroxypropyl                                                           4-(3'-p-chloro-     24    42  41  63            30                            benzoyl-phenyl)-                                                              butyrate                                                                      4-(m-benzoyl-phenyl)                                                          3-hydroxy-butyric                                                                            5    60    58  80  95             5                            acid                                                                          ethyl 4-(m-benzoyl-                                                           phenyl)-3-hydroxy-                                                                           4    44    42  66  90            15                            butyrate                                                                      2,3-isopropylidene-                                                           dioxypropyl 4-(m-             37  44  76        50                            benzoyl-phenyl)-                                                              butyrate                                                                      4-(m-benzoyl-phenyl)                                                          2-methyl-butyric acid         31  45  50   87   100                           4-(3'-p-chloroben-                                                            zoyl-2'-methyl-phenyl)    33  57  82            20                            butyric acid                                                                  4-(3'-p-chloroben-                                                            zoyl-phenyl)-butyric          17  53  68   76   50                            acid                                                                          2,3-isopropylidene-                             20                            dioxypropyl 4-(m-benz-        50  44  70        to                            oyl-phenyl)-2-methyl-                           50                            butyrate                                                                      2,3-dihydroxypropyl                                                           4-(m-benzoyl-phenyl)              28  26   45   200                           2-methyl-butyrate                                                             ______________________________________                                    

C. Ulcerigenic Activity

The ulcerigenic activity was determined by a test inspired by Boissieret al. [Ther., Vol. 22 (1967), p. 157]. Female rats weighing between 120and 140 g were starved for the 24 hours before the start of the test andthe test products were administered orally in an aqueous suspension of0.4 ml per 100 g of animal weight and at varying dosages. The animalswere sacrified 7 hours after the treatment or 31 hours after thebeginning of starvation and the stomachs were removed. The importance ofulcerous lesions was evaluated for each stomach taking into account thenumber and sizes. The results are summarized in the following Table.

    ______________________________________                                                             Average Ulcerigenic                                             Products      dose in mg/kg                                            ______________________________________                                        4-(m-benzoyl-phenyl)butyric acid                                                                   >300                                                     2,3-isopropylidenedioxypropyl                                                 4-(3'-p-chlorobenzoyl-2'-methyl-                                              phenyl)-butyrate     >300                                                     2,3-isopropylidenedioxypropyl                                                 4-(3'-p-chlorobenzoyl-phenyl)-                                                butyrate             >300                                                     2,3-dihydroxypropyl 4-(3'-p-                                                  chlorobenzoyl-2'-methyl-phenyl)-                                              butyrate             300                                                      2,3-dihydroxypropyl 4-(m-benzoyl-                                             phenyl)-butyrate     300                                                      2,3-dihydroxypropyl 4-(3'-p-                                                  chlorobenzoyl-phenyl)-butyrate                                                                     >100                                                     4-(m-benzoyl-phenyl)-3-hydroxy-                                               butyric acid         300                                                      Ethyl 4-(m-benzoyl-phenyl)-                                                   3-hydroxy-butyrate   >300                                                     2,3-isopropylidenedioxypropyl                                                 4-(m-benzoyl-phenyl)-butyrate                                                                      >300                                                     4-(3'-p-chlorobenzoyl-2'-                                                     methyl-phenyl)-butyric acid                                                                        >300                                                     4-(3'-p-chlorobenzoyl-phenyl)                                                 butyric acid         > 50                                                     ______________________________________                                    

Various modifications of the products and methods of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is to be limited only as defined in theappended claims.

We claim:
 1. An analgesic and anti-inflammatory composition comprisingan effective amount of a compound selected from the group consisting ofbutyric acid derivative of the formula ##SPC25##wherein X, X₁, X₂ and X₃are individually selected from the group consisting of hydrogen,halogen, lower alkyl of 1 to 5 carbon atoms, lower alkoxy of 1 to 5carbon atoms, lower alkylthio of 1 to 5 carbon atoms, trifluoromethoxy,trifluoromethylthio, trifluoromethyl, OH and dilower alkylamino of 1 to5 carbon atoms for each alkyl, R is selected from the group consistingof hydrogen, lower alkyl of 1 to 5 carbon atoms, o-carboxyphenyl,2,3-dihydroxypropyl and ##EQU2## wherein P and Q are individually loweralkyl of 1 to 5 carbon atoms, Z and X₄ are individually selected fromthe group consisting of hydrogen and lower alkyl of 1 to 5 carbon atomsand Y is selected from the group consisting of hydrogen and --OH and thedotted line indicates the optional presence of a double bond when Y ishydrogen and when R is hydrogen or o-carboxyphenyl, a salt thereof witha non-toxic, pharmaceutically acceptable mineral or organic base and apharmaceutical carrier.
 2. A method of relieving pain and inflammationin warm-blooded animals comprising administering to a warm-bloodedanimal an effective amount of a compound selected from the groupconsisting of butyric acid derivative of the formula ##SPC26##wherein X,X₁, X₂ and X₃ are individually selected from the group consisting ofhydrogen, halogen, lower alkyl of 1 to 5 carbon atoms, lower alkoxy of 1to 5 carbon atoms, lower alkylthio of 1 to 5 carbon atoms,trifluoromethoxy, trifluoromethylthio, trifluoromethyl, OH and diloweralkylamino of 1 to 5 carbon atoms for each alkyl, R is selected from thegroup consisting of hydrogen, lower alkyl of 1 to 5 carbon atoms,o-carboxyphenyl, 2,3-dihydroxypropyl and ##STR11## wherein P and Q areindividually lower alkyl of 1 to 5 carbon atoms, Z and X₄ areindividually selected from the group consisting of hydrogen and loweralkyl of 1 to 5 carbon atoms and Y is selected from the group consistingof hydrogen and --OH and the dotted line indicates the optional presenceof a double bond when Y is hydrogen and when R is hydrogen oro-carboxyphenyl, a salt thereof with a non-toxic, pharmaceuticallyacceptable mineral or organic base.
 3. The method of claim 2 wherein thecompound is selected from the group consisting of4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid and4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-2-butenoic acid.
 4. The methodof claim 2 wherein X₁ and X₃ are hydrogen, X and X₂ are individuallyselected from the group consisting of hydrogen, halogen, lower alkyl of1 to 5 carbon atoms, lower alkoxy of 1 to 5 carbon atoms, loweralkylthio of 1 to 5 carbon atoms, trifluoromethoxy, trifluoromethylthio,trifluoromethyl, R is selected from the group consisting of hydrogen,alkyl of 1 to 5 carbon atoms, 2,3-dihydroxypropyl and ##STR12## whereinP and Q are individually alkyl of 1 to 5 carbon atoms, and X₄, Z and Yhave the definitions of claim
 2. 5. The method of claim 4 wherein thecompound has the formula ##SPC27##wherein X, X₂, X₄, Z and R have thedefinition of claim 4 and salts thereof where R is hydrogen.
 6. Themethod of claim 4 wherein the compound has the formula ##SPC28##whereinX, X₂, X₄, Y, Z and R have the definition of claim 4 and the dotted lineindicates the optional presence of a double bond, when Y is hydrogen, ineither αβ or βγ to the carboxylic group and salts thereof where R ishydrogen.
 7. The method of claim 4 wherein the compound has the formula##SPC29##wherein X, X₂ and R have the definition of claim 4 and saltsthereof where R is hydrogen.